path: root/gnqa/paper1_eval/src/data/responses/general/experts/09.json

{
    "created_at": "2024-06-01T14:33:22.252190Z",
    "data": {
        "amplify": false,
        "answer": "Mitochondrial DNA (mtDNA) is inherited solely from the maternal lineage, unlike nuclear DNA which requires both paternal and maternal contributions. This uniparental transmission of mtDNA is ensured by complex mechanisms that eliminate paternal mitochondria from sperm during fertilization. mtDNA also exhibits a higher mutation rate than nuclear DNA, leading to significant population-level mtDNA polymorphisms. These polymorphisms can be clustered into distinct haplogroups that represent major branch points on the mitochondrial phylogenetic tree. In contrast, nuclear DNA undergoes bi-parental recombination.",
        "context": {
            "0381d0d4-717f-470b-a8d4-562475cf58bb": [
                {
                    "document_id": "0381d0d4-717f-470b-a8d4-562475cf58bb",
                    "text": "Oxidative stress and mitochondrial DNA\n\nNot long after it was discovered that mitochondria have their own genetic apparatus, Harman proposed that mitochondria play a central role in the free radical theory of aging [16].This idea was developed further by Miquel et al. [330], and the notion that mtDNA mutagenesis played a role in aging took hold.The phenotypical importance of mutations in mtDNA was demonstrated by Wallace et al. [331] and Holt et al. [332], who first showed that Leber's hereditary optic neuropathy and mitochondrial myopathies were caused by mtDNA mutations (reviewed in [333]).Because mtDNA is so close to the site of mitochondrial ROS production, it is exposed to considerably higher oxidative stress, resulting in 3-fold higher levels of DNA oxidative damage (the previously quoted 20-fold figure is apparently due to an isolation artifact [334,335]).In the 1990s a series of papers reported that the frequency of mitochondrial DNA deletions increases dramatically with age, being essentially undetectable in young individuals and reaching levels as high as 2% of mtDNA in old individuals.This age-related increase in mtDNA deletions was found in organisms as diverse as worms, mice, and humans (reviewed in [24,336]).The same is also true with mtDNA point mutations [337,338].Certain mtDNA polymorphisms have been found in increased frequency in centenarians, implying a protective effect during aging [339][340][341].Similar protective effects of mtDNA polymorphisms have been reported for the age-related neurodegenerative condition, Parkinson's disease [342]."
                }
            ],
            "21d2cb60-92ab-4fbb-a3a1-85d3424881c1": [
                {
                    "document_id": "21d2cb60-92ab-4fbb-a3a1-85d3424881c1",
                    "text": "\n\nVariation in the structure and function of mitochondria underlies variation in organismal energetics broadly (Seebacher et al., 2010) and evidence for the importance of mitochondrial function in the evolution of natural populations continues to accumulate (Ballard and Melvin, 2010;Glanville et al., 2012;Hicks et al., 2012;Kurbalija Novičić et al., 2015).For example, variation in mitochondrial DNA sequences (mtDNA) can determine whole-organism metabolism, i.e., the rate at which organisms process energy from their environment, a phenomenon widespread across animal taxa (Arnqvist et al., 2010;Ballard et al., 2007;Ballard and Pichaud, 2014;Havird et al., 2019;Hood et al., 2018;James et al., 2016;Wolff et al., 2014).Specifically, mtDNA sequence variants are linked to functional metabolic differences in fish (Chapdelaine et al., 2020;Flight et al., 2011;Healy et al., 2019), birds (Scott et al., 2011), and mammals (Fontanillas et al., 2005), including humans (Amo and Brand, 2007;Dato et al., 2004;Niemi et al., 2003;Tranah et al., 2011).These mtDNA variants are often correlated with environmental factors such as temperature and altitude (Storz et al., 2010).However, other studies attempting to link mitochondrial function to mitochondrial DNA (mtDNA) sequence variation or environmental factors have offered mixed reports (Amo and Brand, 2007;Flight et al., 2011;Fontanillas et al., 2005;Hicks et al., 2012)."
                },
                {
                    "document_id": "21d2cb60-92ab-4fbb-a3a1-85d3424881c1",
                    "text": "\n\nThe results here point to several potentially fruitful research directions.We have identified how nonsynonymous mutations in the mitochondrial genome associate with variation in whole-organism metabolism (including CytB, ND1, ND5 and ND6).A next step will be to characterize the molecular details of how these changes affect molecular function.It would also be beneficial to describe how variation in cellular oxygen consumption rate scales up to determine whole-organism metabolic rate across a range of temperatures, thus identifying potential mismatches across levels of organization that may impact organismal performance (Gangloff and Telemeco, 2018).While the interconnected processes that shape organismal and population-level responses to environmental variation do not lend themselves to simple narratives, and many molecular processes interact to produce the emergent ecotypic divergences at the phenotypic level, it is clear that the mitochondria play a central role even as that role may change across populations and ecological contexts (Fig. 1).Research within well-characterized natural systems, such as these garter snake populations, can offer illustrative case studies of how mitochondria respond to their environments, and thus impact physiological pathways and evolutionary patterns, creating variation in life histories and aging."
                },
                {
                    "document_id": "21d2cb60-92ab-4fbb-a3a1-85d3424881c1",
                    "text": "\n\nDespite the complexities underlying observed variation in mitochondrial function, recent work has demonstrated examples of how evolution and plasticity in mitochondrial function across populations within a species can shape life histories.For example, evidence from Drosophila has demonstrated the effect of temperature on components of the ETC and has linked mtDNA variants to metabolic thermosensitivity (Pichaud et al., 2012), to differences in whole-organism metabolic rates (Kurbalija Novičić et al., 2015), and to fitness-related traits (Ballard et al., 2007;Pichaud et al., 2011;Pichaud et al., 2010).In general, studies in birds and mammals demonstrate that mitochondria of longer-lived species are more efficient in ATP production, produce less reactive oxygen species, and demonstrate increased antioxidant capacities (Barja and Herrero, 2000;Ku et al., 1993;Lambert et al., 2007).While some studies in lizards and snakes demonstrate a similar pattern (Olsson et al., 2008;Robert et al., 2007), the extent to which these results are generalizable across vertebrate taxa is not yet known.The diversity of life-history traits and immense variation in longevity demonstrated by reptiles, both within and among species, make these taxa ideal candidates for understanding how variation in mitochondrial physiology drives this variation in whole-organism traits (reviewed in Hoekstra et al., 2019).Such work has moved to the forefront with a recent focus on the ecological and evolutionary significance of aging processes in wild populations (reviewed in Nussey et al., 2013;Fletcher and Selman, 2015;Gaillard and Lemaître, 2020)."
                },
                {
                    "document_id": "21d2cb60-92ab-4fbb-a3a1-85d3424881c1",
                    "text": "\n\nOver evolutionary time, differential mortality rates are a selective force in shaping genetic structure.This results in divergence of a variety of physiological networks that shape, ultimately, patterns of aging and longevity in different habitats (Monaghan et al., 2008;Stojković et al., 2017).Such selective pressures can have differential effects on the nuclear and mitochondrial genomes (McKenzie et al., 2019;Wolff et al., 2014).Genetic variation in the mitochondrial genome is known to drive mitochondrial function in many species (Ballard and Melvin, 2010;McKenzie et al., 2019;Novelletto et al., 2016) and we find this in our system as well.Whole organism metabolic rate varies with the mitochondrial genome haplogroups we identified in this study.T. elegans individuals with the introgressed T. sirtalis mitochondrial genome had the lowest metabolic rate and had 68 amino acid changes in the ETC genes relative to the T. elegans mitochondrial genomes.As species divergence are a continuation of population divergence, this introgression provides additional insight into how genetic variation can alter mitochondrial function.Whether the lower metabolic rate in our snakes with the introgressed mitochondrial genome is due to the fixed amino acid changes between the species or a mismatch between the coadapted nuclear and mitochondrially-encoded ETC proteins that could alter function of the mitochondria (Burton et al., 2013;Haenel, 2017;Rawson and Burton, 2002;Toews et al., 2014;Wolff et al., 2014) will require further comparisons to T. sirtalis individuals."
                },
                {
                    "document_id": "21d2cb60-92ab-4fbb-a3a1-85d3424881c1",
                    "text": "\n\nBuilding on previous work in this system, the current study tests three primary hypotheses about how variation in mtDNA and mitochondrial function relate to variation in life-history traits and aging within this system (Fig. 1): (1) First, we test whether rates of cellular oxygen consumption in isolated immune cells exhibit patterns that are consistent with the hypothesis that cellular processes drive whole-organism senescence and aging, and if these patterns differ between the SA and FA ecotypes and between sexes.By measuring basal, ATP-production associated, and maximal rates of cellular oxygen consumption, we further test for evidence that phenotypic divergence is dependent on a specific aspect of oxidative phosphorylation within immune cells.The energetics of these cells are particularly important given their essential role in modulating disease and infection, important factors contributing to senescence (Metcalf et al., 2019).We predict that SA snakes will maintain levels of cellular oxygen consumption across age, whereas the FA snakes will show a decline with age, especially in ATP-associated rates, possibly due to continual degradation of electron transport chain functionality from accumulating oxidative damage and reduced DNA repair mechanisms (Robert and Bronikowski, 2010;Schwartz and Bronikowski, 2013). ( 2) Second, we expand our mitochondrial genomics dataset to quantify mtDNA genetic structure across the landscape and test whether mtDNA haplotypes, and alleles at a nonsynonymous SNP in the Cytochrome B (CytB) gene correlate with aging ecotypes. (3) Third, we test the hypothesis that variation in mtDNA correlates with whole-organism variation in metabolic rates, suggesting a pathway linking mitochondrial genetic variation in mtDNA to whole-organism energetics.We first test whether different haplotypes differ in resting metabolic rate.Then, we test the effects of the nonsynonymous SNP in CytB on resting metabolic rate.The CytB gene encodes a component of complex III of the ETC, and was previously found to segregate between these life-history ecotypes (Schwartz et al., 2015).This SNP results in an amino acid substitution from isoleucine (aliphatic, hydrophobic) to threonine (hydrophilic) on a region that comes into close contact with a nuclear-encoded subunit (Schwartz et al., 2015).We combine previously published and new data on whole-organism resting metabolic rates (oxygen consumption) to test for the effects of this nonsynonymous mutation in three populations where we find heterogeneity at this nucleotide, thus allowing us to disentangle the effects of shared environment (population) from sequence variation (SNP).We predict that this SNP will correlate with variation in whole-organism metabolic rate, demonstrating a putatively adaptive difference between the derived and ancestral sequence.By utilizing this integrative data setfrom genes to organelles to whole organisms to populationsin a known life-history context, we are able to test hypotheses across levels of organization to provide a more complete picture of the complicated story of mitochondria and life history (Havird et al., 2019)."
                }
            ],
            "253fad94-3be6-4362-b56f-f00c9c5705e6": [
                {
                    "document_id": "253fad94-3be6-4362-b56f-f00c9c5705e6",
                    "text": "mtDNA Diversity\n\nUnlike the nuclear genome, which requires both paternal and maternal contributions, mtDNA is inherited solely from the maternal lineage.It is unclear what advantage a uniparental mtDNA transmission confers, but one possibility is to minimize the number of distinct genomes to maximize the efficiency of a multi-genomic system (Hill et al. 2019).In fact, humans have developed complex, redundant mechanisms to ensure uniparental inheritance of mtDNA (DeLuca and O'Farrell 2012; Rojansky et al. 2016).Paternal mitochondria from sperms that enter into the egg during fertilization are actively and selectively eliminated via mitophagy through two E3 ligases, PARKIN, and MUL1 (Rojansky et al. 2016).PARKIN and MUL1 serve redundant purposes, and mitophagy becomes insufficient to eliminate paternal mtDNA only in the absence of both (Rojansky et al. 2016).Even though oocytes have  at least a thousand-fold more mitochondria than a sperm cell (Rojansky et al. 2016) and heteroplasmy levels would be very low if paternal mtDNA were to contaminate the embryo, the results can still be non-trivial.However, challenging this notion, a recent study provides evidence of potential paternal transmission (Luo et al. 2018), but awaits further corroborating studies (Lutz-Bonengel and Parson 2019)."
                },
                {
                    "document_id": "253fad94-3be6-4362-b56f-f00c9c5705e6",
                    "text": "\n\nMtDNA exhibit a higher mutation rate than nuclear DNA, leading to significant population-level mtDNA polymorphisms (van Oven and Kayser 2009; Wallace 1999; Wallace and Chalkia 2013).In fact, the co-evolution of the mitonuclear genomes has been proposed to be driven by mtDNA mutations that select for compensatory changes in the nuclear genome (Havird and Sloan 2016).Populations that share similar mtDNA polymorphisms can be clustered into distinct haplogroups that are designated using all letters of the alphabet (i.e., A through Z).The mtDNA haplogroups represent major branch points on the mitochondrial phylogenetic tree that have strong regional ties around the globe, thus supporting the concept of a 'mitochondrial eve' (Wallace 1999).Haplogroups present inherently different mitonuclear interactions (Zaidi and Makova 2019), which eventually affect the aging process (Wolff et al. 2016).For example, one haplogroup commonly found in Ashkenazi Jews can interact with a specific enrichment of an amino acid sequence in complex I, and result in altered susceptibility to type 2 diabetes mellitus (Gershoni et al. 2014).The effect of mitonuclear compatibility on lifespan is influenced by environmental cues in flies (Drummond et al. 2019).It is unclear if mitonuclear compatibility is invariable throughout an organism's life, or antagonistically pleiotropic during aging, making it a difficult moving target to understand."
                }
            ],
            "2f39f55f-2604-49d4-9589-0e1403b84d7a": [
                {
                    "document_id": "2f39f55f-2604-49d4-9589-0e1403b84d7a",
                    "text": "\n\nBackground: The accumulation of mitochondrial DNA (mtDNA) mutations, and the reduction of mtDNA copy number, both disrupt mitochondrial energetics, and may contribute to aging and age-associated phenotypes.However, there are few genetic and epidemiological studies on the spectra of blood mtDNA heteroplasmies, and the distribution of mtDNA copy numbers in different age groups and their impact on age-related phenotypes.In this work, we used whole-genome sequencing data of isolated peripheral blood mononuclear cells (PBMCs) from the UK10K project to investigate in parallel mtDNA heteroplasmy and copy number in 1511 women, between 17 and 85 years old, recruited in the TwinsUK cohorts."
                }
            ],
            "4a17ce5c-55df-4aa0-a664-f6a03238d332": [
                {
                    "document_id": "4a17ce5c-55df-4aa0-a664-f6a03238d332",
                    "text": "Discussion\n\nTwo significant questions are raised by the findings that mitochondrial DNA can integrate into the nucleus.Firstly, is this an extraordinarily rare event or is it occurring continually and at high frequency?Secondly, can such an event have pathological consequences to the organism?"
                }
            ],
            "4f010a74-a9b4-4538-94f7-ae8f35c8b96e": [
                {
                    "document_id": "4f010a74-a9b4-4538-94f7-ae8f35c8b96e",
                    "text": "Phylogeny\n\nThe mtDNA is maternally inherited (120) by offspring through the oocyte cytoplasm; namely, the mother transmits her mtDNAs to all of her offspring, and her daughters transmit their mtDNAs to the next generation.This is the consequence of the fact that the mature oocyte such as mouse (304) or bovine (144) contains lOO-1,000 times more mtDNA than is found in somatic cells.Hence, the few sperm mtDNAs that enter the egg (130) have little effect on the genotype.The maternal inheritance results in sequentially diverged mtDNA polymorphism of modern human, as shown in Figure 2. The polymorphism derives from the combinations of small deletions and additions of <14 bp in noncoding region and base substitutions including some point mutations in coding region."
                },
                {
                    "document_id": "4f010a74-a9b4-4538-94f7-ae8f35c8b96e",
                    "text": "\n\nThere have been few reports on distinct correlation between mitochondrial morphology and human aging, except changes in number and size of mitochondria associated with age.Concerning the gross structure of mitochondria, the overwhelming importance of the cell nucleus in mitochondrial biogenesis should be noted, because the major parts of mitochondrial proteins are encoded by nuclear genes that are stable during life with the efficient repair mechanism for nDNA."
                },
                {
                    "document_id": "4f010a74-a9b4-4538-94f7-ae8f35c8b96e",
                    "text": "\n\nEarly data on DNA polymorphism detected by restriction endonuclease (263) have suggested that the evolutionary change of mtDNA in higher animals occurs mainly by nucleotide substitution rather than by deletion and insertion.The mtDNA nucleotide sequence evolves 6-17 times faster than comparable nuclear DNA gene sequences (51,52,405).Rapid evolution of mtDNA of higher primates including human, 0.02 base substitutions per site per million years, was calculated from the restriction map of mtDNA (51).Because orthodox recombination mechanism appears to be absent in mtDNA (128), germline mutation seems to go down to posterity as maternal inheritance from our common ancestor (57)."
                }
            ],
            "612a70c6-2f42-492f-9f23-0d5e9296919e": [
                {
                    "document_id": "612a70c6-2f42-492f-9f23-0d5e9296919e",
                    "text": "\n\nA number of conclusions may be drawn from these results.Firstly, the data begin to answer the question of how closely mtDNA replication is kept in synchrony with nuclear DNA replication: it would appear to be regulated not by direct coupling to the nuclear DNA replication, but rather by the cell mass to be serviced by mitochondria."
                }
            ],
            "65c8287b-eb19-437a-b9ca-5aaa8664d429": [
                {
                    "document_id": "65c8287b-eb19-437a-b9ca-5aaa8664d429",
                    "text": "\n\nIt may be that high mtDNA levels are indeed indicative of compromised mitochondria, but that the underlying defects are unrelated to alterations in the DNA sequence.Alternatively, elevated quantities of mtDNA might be associated with increased metabolic requirements of the embryo, rather than organelles of suboptimal function.It is possible that embryos produced by older oocytes are under some form of stress and therefore have larger energy requirements.Functional experiments will be required to address these questions.Whatever the underlying basis, the current study has unequivocally demonstrated that female reproductive aging is associated with changes in the mtDNA content at the blastocyst stage."
                }
            ],
            "67ec2631-aa17-436e-800b-1bc046fb5b19": [
                {
                    "document_id": "67ec2631-aa17-436e-800b-1bc046fb5b19",
                    "text": "\n\nAge-associated alterations of the mitochondrial genome occur in several different species; however, their physiological relevance remains unclear.The age-associated changes of mitochondrial DNA (mtDNA) include nucleotide point mutations and modifications, as well as deletions.In this review, we summarize the current literature on age-associated mtDNA mutations and deletions and comment on their abundance.A clear need exists for a more thorough evaluation of the total damage to the mitochondrial genome that accumulates in aged tissues.᭧ 1997 Elsevier Science Inc."
                }
            ],
            "8a9fe1bc-7fa3-40ee-ade0-9a498bcf9def": [
                {
                    "document_id": "8a9fe1bc-7fa3-40ee-ade0-9a498bcf9def",
                    "text": "Mitochondrial genetics\n\nOne underexplored avenue for determining maternal risk for preterm birth involves the influence of the mitochondrial genome.The high mutation rate of mito chondrial DNA (mtDNA), together with the fact that most of its encoded proteins are evolutionarily con served, allowing for the selection of neutral or beneficial variants, has generated interest in defining human mtDNA variations and their roles in human biology [58]."
                }
            ],
            "aa942230-9a43-4b5f-90d9-96d364861a57": [
                {
                    "document_id": "aa942230-9a43-4b5f-90d9-96d364861a57",
                    "text": "\n\nClearly, as mitochondrial metabolic and genetic therapies advance for treating mitochondrial disease, they will also be available to enhance the personal lives of others.However, mitochondrial genetic variation appears to have been one of the primary factors that permitted our ancestors to adapt to new environments, survive adverse conditions, and multiple throughout the globe.Is it possible that by taking over control of individual mtDNA variation, we might also be setting our species on the road to functional decline and ultimately extinction?"
                },
                {
                    "document_id": "aa942230-9a43-4b5f-90d9-96d364861a57",
                    "text": "Mitochondrial therapeutics and performance enhancement\n\nIt is now clear that not all mtDNA variation is deleterious.Indeed, about 25% of all ancient mtDNA variation appears to have caused functional mitochondrial changes and thus been adaptive.Those mtDNA variants that are adapted to warm climates have mtDNA variants that result in tightly coupled OXPHOS, thus maximizing ATP output and minimizing heat production.The presence of these mtDNAs permits maximum muscle performance but also predispose sedentary individuals that consume excess calories to multiple problems.They would be prone to be overweight and their mitochondria would generate excessive ROS, thus making them susceptible to a variety of degenerative diseases, cancer and premature aging.Partially uncoupled mitochondria generate more heat, but at the expense of ATP production.Individual's with these variants are better able to tolerate the cold, and are less prone to obesity.They also generate less ROS making then resistant to degenerative diseases and aging.Finally, the mitochondria are why we breathe.Hence, mitochondrial variation might be an important factor in individual predisposition to altitude sickness."
                }
            ],
            "b0af29ac-0997-416d-907a-6caba940536d": [
                {
                    "document_id": "b0af29ac-0997-416d-907a-6caba940536d",
                    "text": "\n\nHuman mtDNA codes for 13 essential polypeptide components of the mitochondrial oxidative phosphorylation (OXPHOS) system.mtDNA undergoes strict maternal inheritance, resulting in the absence of bi-parental recombination (Elson et al., 2001) and has a high mutation rate (Tuppen et al., 2010).As such, the evolution of mtDNA is characterised by the emergence of distinct lineages (or haplogroups) (Hernstadt et al., 2002).This results in high levels of mtDNA variation at the population level despite its rather small size, which is also illustrated by the large number of sub-haplogroups (van Oven and Kayser, 2009).Africa"
                }
            ]
        },
        "data_source": [
            {
                "document_id": "253fad94-3be6-4362-b56f-f00c9c5705e6",
                "section_type": "main",
                "text": "mtDNA Diversity\n\nUnlike the nuclear genome, which requires both paternal and maternal contributions, mtDNA is inherited solely from the maternal lineage.It is unclear what advantage a uniparental mtDNA transmission confers, but one possibility is to minimize the number of distinct genomes to maximize the efficiency of a multi-genomic system (Hill et al. 2019).In fact, humans have developed complex, redundant mechanisms to ensure uniparental inheritance of mtDNA (DeLuca and O'Farrell 2012; Rojansky et al. 2016).Paternal mitochondria from sperms that enter into the egg during fertilization are actively and selectively eliminated via mitophagy through two E3 ligases, PARKIN, and MUL1 (Rojansky et al. 2016).PARKIN and MUL1 serve redundant purposes, and mitophagy becomes insufficient to eliminate paternal mtDNA only in the absence of both (Rojansky et al. 2016).Even though oocytes have  at least a thousand-fold more mitochondria than a sperm cell (Rojansky et al. 2016) and heteroplasmy levels would be very low if paternal mtDNA were to contaminate the embryo, the results can still be non-trivial.However, challenging this notion, a recent study provides evidence of potential paternal transmission (Luo et al. 2018), but awaits further corroborating studies (Lutz-Bonengel and Parson 2019)."
            },
            {
                "document_id": "21d2cb60-92ab-4fbb-a3a1-85d3424881c1",
                "section_type": "main",
                "text": "\n\nVariation in the structure and function of mitochondria underlies variation in organismal energetics broadly (Seebacher et al., 2010) and evidence for the importance of mitochondrial function in the evolution of natural populations continues to accumulate (Ballard and Melvin, 2010;Glanville et al., 2012;Hicks et al., 2012;Kurbalija Novičić et al., 2015).For example, variation in mitochondrial DNA sequences (mtDNA) can determine whole-organism metabolism, i.e., the rate at which organisms process energy from their environment, a phenomenon widespread across animal taxa (Arnqvist et al., 2010;Ballard et al., 2007;Ballard and Pichaud, 2014;Havird et al., 2019;Hood et al., 2018;James et al., 2016;Wolff et al., 2014).Specifically, mtDNA sequence variants are linked to functional metabolic differences in fish (Chapdelaine et al., 2020;Flight et al., 2011;Healy et al., 2019), birds (Scott et al., 2011), and mammals (Fontanillas et al., 2005), including humans (Amo and Brand, 2007;Dato et al., 2004;Niemi et al., 2003;Tranah et al., 2011).These mtDNA variants are often correlated with environmental factors such as temperature and altitude (Storz et al., 2010).However, other studies attempting to link mitochondrial function to mitochondrial DNA (mtDNA) sequence variation or environmental factors have offered mixed reports (Amo and Brand, 2007;Flight et al., 2011;Fontanillas et al., 2005;Hicks et al., 2012)."
            },
            {
                "document_id": "253fad94-3be6-4362-b56f-f00c9c5705e6",
                "section_type": "main",
                "text": "\n\nMtDNA exhibit a higher mutation rate than nuclear DNA, leading to significant population-level mtDNA polymorphisms (van Oven and Kayser 2009; Wallace 1999; Wallace and Chalkia 2013).In fact, the co-evolution of the mitonuclear genomes has been proposed to be driven by mtDNA mutations that select for compensatory changes in the nuclear genome (Havird and Sloan 2016).Populations that share similar mtDNA polymorphisms can be clustered into distinct haplogroups that are designated using all letters of the alphabet (i.e., A through Z).The mtDNA haplogroups represent major branch points on the mitochondrial phylogenetic tree that have strong regional ties around the globe, thus supporting the concept of a 'mitochondrial eve' (Wallace 1999).Haplogroups present inherently different mitonuclear interactions (Zaidi and Makova 2019), which eventually affect the aging process (Wolff et al. 2016).For example, one haplogroup commonly found in Ashkenazi Jews can interact with a specific enrichment of an amino acid sequence in complex I, and result in altered susceptibility to type 2 diabetes mellitus (Gershoni et al. 2014).The effect of mitonuclear compatibility on lifespan is influenced by environmental cues in flies (Drummond et al. 2019).It is unclear if mitonuclear compatibility is invariable throughout an organism's life, or antagonistically pleiotropic during aging, making it a difficult moving target to understand."
            },
            {
                "document_id": "4f010a74-a9b4-4538-94f7-ae8f35c8b96e",
                "section_type": "main",
                "text": "Phylogeny\n\nThe mtDNA is maternally inherited (120) by offspring through the oocyte cytoplasm; namely, the mother transmits her mtDNAs to all of her offspring, and her daughters transmit their mtDNAs to the next generation.This is the consequence of the fact that the mature oocyte such as mouse (304) or bovine (144) contains lOO-1,000 times more mtDNA than is found in somatic cells.Hence, the few sperm mtDNAs that enter the egg (130) have little effect on the genotype.The maternal inheritance results in sequentially diverged mtDNA polymorphism of modern human, as shown in Figure 2. The polymorphism derives from the combinations of small deletions and additions of <14 bp in noncoding region and base substitutions including some point mutations in coding region."
            },
            {
                "document_id": "21d2cb60-92ab-4fbb-a3a1-85d3424881c1",
                "section_type": "main",
                "text": "\n\nThe results here point to several potentially fruitful research directions.We have identified how nonsynonymous mutations in the mitochondrial genome associate with variation in whole-organism metabolism (including CytB, ND1, ND5 and ND6).A next step will be to characterize the molecular details of how these changes affect molecular function.It would also be beneficial to describe how variation in cellular oxygen consumption rate scales up to determine whole-organism metabolic rate across a range of temperatures, thus identifying potential mismatches across levels of organization that may impact organismal performance (Gangloff and Telemeco, 2018).While the interconnected processes that shape organismal and population-level responses to environmental variation do not lend themselves to simple narratives, and many molecular processes interact to produce the emergent ecotypic divergences at the phenotypic level, it is clear that the mitochondria play a central role even as that role may change across populations and ecological contexts (Fig. 1).Research within well-characterized natural systems, such as these garter snake populations, can offer illustrative case studies of how mitochondria respond to their environments, and thus impact physiological pathways and evolutionary patterns, creating variation in life histories and aging."
            },
            {
                "document_id": "21d2cb60-92ab-4fbb-a3a1-85d3424881c1",
                "section_type": "main",
                "text": "\n\nDespite the complexities underlying observed variation in mitochondrial function, recent work has demonstrated examples of how evolution and plasticity in mitochondrial function across populations within a species can shape life histories.For example, evidence from Drosophila has demonstrated the effect of temperature on components of the ETC and has linked mtDNA variants to metabolic thermosensitivity (Pichaud et al., 2012), to differences in whole-organism metabolic rates (Kurbalija Novičić et al., 2015), and to fitness-related traits (Ballard et al., 2007;Pichaud et al., 2011;Pichaud et al., 2010).In general, studies in birds and mammals demonstrate that mitochondria of longer-lived species are more efficient in ATP production, produce less reactive oxygen species, and demonstrate increased antioxidant capacities (Barja and Herrero, 2000;Ku et al., 1993;Lambert et al., 2007).While some studies in lizards and snakes demonstrate a similar pattern (Olsson et al., 2008;Robert et al., 2007), the extent to which these results are generalizable across vertebrate taxa is not yet known.The diversity of life-history traits and immense variation in longevity demonstrated by reptiles, both within and among species, make these taxa ideal candidates for understanding how variation in mitochondrial physiology drives this variation in whole-organism traits (reviewed in Hoekstra et al., 2019).Such work has moved to the forefront with a recent focus on the ecological and evolutionary significance of aging processes in wild populations (reviewed in Nussey et al., 2013;Fletcher and Selman, 2015;Gaillard and Lemaître, 2020)."
            },
            {
                "document_id": "4a17ce5c-55df-4aa0-a664-f6a03238d332",
                "section_type": "main",
                "text": "Discussion\n\nTwo significant questions are raised by the findings that mitochondrial DNA can integrate into the nucleus.Firstly, is this an extraordinarily rare event or is it occurring continually and at high frequency?Secondly, can such an event have pathological consequences to the organism?"
            },
            {
                "document_id": "612a70c6-2f42-492f-9f23-0d5e9296919e",
                "section_type": "main",
                "text": "\n\nA number of conclusions may be drawn from these results.Firstly, the data begin to answer the question of how closely mtDNA replication is kept in synchrony with nuclear DNA replication: it would appear to be regulated not by direct coupling to the nuclear DNA replication, but rather by the cell mass to be serviced by mitochondria."
            },
            {
                "document_id": "b0af29ac-0997-416d-907a-6caba940536d",
                "section_type": "main",
                "text": "\n\nHuman mtDNA codes for 13 essential polypeptide components of the mitochondrial oxidative phosphorylation (OXPHOS) system.mtDNA undergoes strict maternal inheritance, resulting in the absence of bi-parental recombination (Elson et al., 2001) and has a high mutation rate (Tuppen et al., 2010).As such, the evolution of mtDNA is characterised by the emergence of distinct lineages (or haplogroups) (Hernstadt et al., 2002).This results in high levels of mtDNA variation at the population level despite its rather small size, which is also illustrated by the large number of sub-haplogroups (van Oven and Kayser, 2009).Africa"
            },
            {
                "document_id": "2f39f55f-2604-49d4-9589-0e1403b84d7a",
                "section_type": "main",
                "text": "\n\nBackground: The accumulation of mitochondrial DNA (mtDNA) mutations, and the reduction of mtDNA copy number, both disrupt mitochondrial energetics, and may contribute to aging and age-associated phenotypes.However, there are few genetic and epidemiological studies on the spectra of blood mtDNA heteroplasmies, and the distribution of mtDNA copy numbers in different age groups and their impact on age-related phenotypes.In this work, we used whole-genome sequencing data of isolated peripheral blood mononuclear cells (PBMCs) from the UK10K project to investigate in parallel mtDNA heteroplasmy and copy number in 1511 women, between 17 and 85 years old, recruited in the TwinsUK cohorts."
            },
            {
                "document_id": "0381d0d4-717f-470b-a8d4-562475cf58bb",
                "section_type": "main",
                "text": "Oxidative stress and mitochondrial DNA\n\nNot long after it was discovered that mitochondria have their own genetic apparatus, Harman proposed that mitochondria play a central role in the free radical theory of aging [16].This idea was developed further by Miquel et al. [330], and the notion that mtDNA mutagenesis played a role in aging took hold.The phenotypical importance of mutations in mtDNA was demonstrated by Wallace et al. [331] and Holt et al. [332], who first showed that Leber's hereditary optic neuropathy and mitochondrial myopathies were caused by mtDNA mutations (reviewed in [333]).Because mtDNA is so close to the site of mitochondrial ROS production, it is exposed to considerably higher oxidative stress, resulting in 3-fold higher levels of DNA oxidative damage (the previously quoted 20-fold figure is apparently due to an isolation artifact [334,335]).In the 1990s a series of papers reported that the frequency of mitochondrial DNA deletions increases dramatically with age, being essentially undetectable in young individuals and reaching levels as high as 2% of mtDNA in old individuals.This age-related increase in mtDNA deletions was found in organisms as diverse as worms, mice, and humans (reviewed in [24,336]).The same is also true with mtDNA point mutations [337,338].Certain mtDNA polymorphisms have been found in increased frequency in centenarians, implying a protective effect during aging [339][340][341].Similar protective effects of mtDNA polymorphisms have been reported for the age-related neurodegenerative condition, Parkinson's disease [342]."
            },
            {
                "document_id": "21d2cb60-92ab-4fbb-a3a1-85d3424881c1",
                "section_type": "main",
                "text": "\n\nOver evolutionary time, differential mortality rates are a selective force in shaping genetic structure.This results in divergence of a variety of physiological networks that shape, ultimately, patterns of aging and longevity in different habitats (Monaghan et al., 2008;Stojković et al., 2017).Such selective pressures can have differential effects on the nuclear and mitochondrial genomes (McKenzie et al., 2019;Wolff et al., 2014).Genetic variation in the mitochondrial genome is known to drive mitochondrial function in many species (Ballard and Melvin, 2010;McKenzie et al., 2019;Novelletto et al., 2016) and we find this in our system as well.Whole organism metabolic rate varies with the mitochondrial genome haplogroups we identified in this study.T. elegans individuals with the introgressed T. sirtalis mitochondrial genome had the lowest metabolic rate and had 68 amino acid changes in the ETC genes relative to the T. elegans mitochondrial genomes.As species divergence are a continuation of population divergence, this introgression provides additional insight into how genetic variation can alter mitochondrial function.Whether the lower metabolic rate in our snakes with the introgressed mitochondrial genome is due to the fixed amino acid changes between the species or a mismatch between the coadapted nuclear and mitochondrially-encoded ETC proteins that could alter function of the mitochondria (Burton et al., 2013;Haenel, 2017;Rawson and Burton, 2002;Toews et al., 2014;Wolff et al., 2014) will require further comparisons to T. sirtalis individuals."
            },
            {
                "document_id": "4f010a74-a9b4-4538-94f7-ae8f35c8b96e",
                "section_type": "main",
                "text": "\n\nThere have been few reports on distinct correlation between mitochondrial morphology and human aging, except changes in number and size of mitochondria associated with age.Concerning the gross structure of mitochondria, the overwhelming importance of the cell nucleus in mitochondrial biogenesis should be noted, because the major parts of mitochondrial proteins are encoded by nuclear genes that are stable during life with the efficient repair mechanism for nDNA."
            },
            {
                "document_id": "4f010a74-a9b4-4538-94f7-ae8f35c8b96e",
                "section_type": "main",
                "text": "\n\nEarly data on DNA polymorphism detected by restriction endonuclease (263) have suggested that the evolutionary change of mtDNA in higher animals occurs mainly by nucleotide substitution rather than by deletion and insertion.The mtDNA nucleotide sequence evolves 6-17 times faster than comparable nuclear DNA gene sequences (51,52,405).Rapid evolution of mtDNA of higher primates including human, 0.02 base substitutions per site per million years, was calculated from the restriction map of mtDNA (51).Because orthodox recombination mechanism appears to be absent in mtDNA (128), germline mutation seems to go down to posterity as maternal inheritance from our common ancestor (57)."
            },
            {
                "document_id": "65c8287b-eb19-437a-b9ca-5aaa8664d429",
                "section_type": "main",
                "text": "\n\nIt may be that high mtDNA levels are indeed indicative of compromised mitochondria, but that the underlying defects are unrelated to alterations in the DNA sequence.Alternatively, elevated quantities of mtDNA might be associated with increased metabolic requirements of the embryo, rather than organelles of suboptimal function.It is possible that embryos produced by older oocytes are under some form of stress and therefore have larger energy requirements.Functional experiments will be required to address these questions.Whatever the underlying basis, the current study has unequivocally demonstrated that female reproductive aging is associated with changes in the mtDNA content at the blastocyst stage."
            },
            {
                "document_id": "21d2cb60-92ab-4fbb-a3a1-85d3424881c1",
                "section_type": "main",
                "text": "\n\nBuilding on previous work in this system, the current study tests three primary hypotheses about how variation in mtDNA and mitochondrial function relate to variation in life-history traits and aging within this system (Fig. 1): (1) First, we test whether rates of cellular oxygen consumption in isolated immune cells exhibit patterns that are consistent with the hypothesis that cellular processes drive whole-organism senescence and aging, and if these patterns differ between the SA and FA ecotypes and between sexes.By measuring basal, ATP-production associated, and maximal rates of cellular oxygen consumption, we further test for evidence that phenotypic divergence is dependent on a specific aspect of oxidative phosphorylation within immune cells.The energetics of these cells are particularly important given their essential role in modulating disease and infection, important factors contributing to senescence (Metcalf et al., 2019).We predict that SA snakes will maintain levels of cellular oxygen consumption across age, whereas the FA snakes will show a decline with age, especially in ATP-associated rates, possibly due to continual degradation of electron transport chain functionality from accumulating oxidative damage and reduced DNA repair mechanisms (Robert and Bronikowski, 2010;Schwartz and Bronikowski, 2013). ( 2) Second, we expand our mitochondrial genomics dataset to quantify mtDNA genetic structure across the landscape and test whether mtDNA haplotypes, and alleles at a nonsynonymous SNP in the Cytochrome B (CytB) gene correlate with aging ecotypes. (3) Third, we test the hypothesis that variation in mtDNA correlates with whole-organism variation in metabolic rates, suggesting a pathway linking mitochondrial genetic variation in mtDNA to whole-organism energetics.We first test whether different haplotypes differ in resting metabolic rate.Then, we test the effects of the nonsynonymous SNP in CytB on resting metabolic rate.The CytB gene encodes a component of complex III of the ETC, and was previously found to segregate between these life-history ecotypes (Schwartz et al., 2015).This SNP results in an amino acid substitution from isoleucine (aliphatic, hydrophobic) to threonine (hydrophilic) on a region that comes into close contact with a nuclear-encoded subunit (Schwartz et al., 2015).We combine previously published and new data on whole-organism resting metabolic rates (oxygen consumption) to test for the effects of this nonsynonymous mutation in three populations where we find heterogeneity at this nucleotide, thus allowing us to disentangle the effects of shared environment (population) from sequence variation (SNP).We predict that this SNP will correlate with variation in whole-organism metabolic rate, demonstrating a putatively adaptive difference between the derived and ancestral sequence.By utilizing this integrative data setfrom genes to organelles to whole organisms to populationsin a known life-history context, we are able to test hypotheses across levels of organization to provide a more complete picture of the complicated story of mitochondria and life history (Havird et al., 2019)."
            },
            {
                "document_id": "aa942230-9a43-4b5f-90d9-96d364861a57",
                "section_type": "main",
                "text": "\n\nClearly, as mitochondrial metabolic and genetic therapies advance for treating mitochondrial disease, they will also be available to enhance the personal lives of others.However, mitochondrial genetic variation appears to have been one of the primary factors that permitted our ancestors to adapt to new environments, survive adverse conditions, and multiple throughout the globe.Is it possible that by taking over control of individual mtDNA variation, we might also be setting our species on the road to functional decline and ultimately extinction?"
            },
            {
                "document_id": "aa942230-9a43-4b5f-90d9-96d364861a57",
                "section_type": "main",
                "text": "Mitochondrial therapeutics and performance enhancement\n\nIt is now clear that not all mtDNA variation is deleterious.Indeed, about 25% of all ancient mtDNA variation appears to have caused functional mitochondrial changes and thus been adaptive.Those mtDNA variants that are adapted to warm climates have mtDNA variants that result in tightly coupled OXPHOS, thus maximizing ATP output and minimizing heat production.The presence of these mtDNAs permits maximum muscle performance but also predispose sedentary individuals that consume excess calories to multiple problems.They would be prone to be overweight and their mitochondria would generate excessive ROS, thus making them susceptible to a variety of degenerative diseases, cancer and premature aging.Partially uncoupled mitochondria generate more heat, but at the expense of ATP production.Individual's with these variants are better able to tolerate the cold, and are less prone to obesity.They also generate less ROS making then resistant to degenerative diseases and aging.Finally, the mitochondria are why we breathe.Hence, mitochondrial variation might be an important factor in individual predisposition to altitude sickness."
            },
            {
                "document_id": "67ec2631-aa17-436e-800b-1bc046fb5b19",
                "section_type": "main",
                "text": "\n\nAge-associated alterations of the mitochondrial genome occur in several different species; however, their physiological relevance remains unclear.The age-associated changes of mitochondrial DNA (mtDNA) include nucleotide point mutations and modifications, as well as deletions.In this review, we summarize the current literature on age-associated mtDNA mutations and deletions and comment on their abundance.A clear need exists for a more thorough evaluation of the total damage to the mitochondrial genome that accumulates in aged tissues.᭧ 1997 Elsevier Science Inc."
            },
            {
                "document_id": "21d2cb60-92ab-4fbb-a3a1-85d3424881c1",
                "section_type": "main",
                "text": "\n\nWorking within a generalized framework that integrates the environmental pressures driving the evolution of metabolic rates and lifehistories can provide insight into how these traits are integrated.In Fig. 1A we present such a framework.Central to this framework, and the best place to start our investigation of these complex interactions across scales and across lifespans, is the mitochondrion.In the cells of eukaryotes, the overwhelming majority of energy substrate (adenosine triphosphate; ATP) to sustain life's functions is produced in mitochondria via oxidative phosphorylation in the electron transport chain (reviewed in Hood et al., 2018;Solaini et al., 2010).Yet these mitochondria must carefully balance their energetic and oxygen demands, their capacity to meet cellular need for ATP, and their production of potentially toxic and harmful byproducts (Barja, 2002;Barja, 2004;Harmon, 1956;Lee and Wei, 2012;Muller et al., 2007).On one hand, energy flow through mitochondria can determine the pace of life of an individual, with implications for lifespan and 'rate of living'.On the other hand, the production of damaging reactive oxygen species (ROS) molecules is implicated in reduced performance and decline during old age, leading to the free radical theory of aging (or oxidative stress theory of aging; Balaban et al., 2005;Barja, 2002;Lyons and Kozak, 2019;Robert et al., 2007;Speakman, 2005).In addition, mitochondria possess a genome that encodes core peptides to electron transport chain (ETC) protein complexes along with nuclear-encoded mitochondrial proteins (Rand et al., 2004;Sunnucks et al., 2017;Wolff et al., 2014).This maternally inherited mitochondrial genome is subject to extensive replication across its lifetime and is linked to aging phenotypes independent of the production of damage-causing reactive oxygen species (Pinto and Moraes, 2015;Seo and Leeuwenburgh, 2015).For these reasons, any variation in mitochondrial function, especially if it is sexor age-dependent, will have ramifications for the evolution of life histories (Dowling and Simmons, 2009;Finkel and Holbrook, 2000;Fletcher et al., 2013;Wikelski and Ricklefs, 2001;Wolff et al., 2016)."
            },
            {
                "document_id": "67ec2631-aa17-436e-800b-1bc046fb5b19",
                "section_type": "abstract",
                "text": "\nAge-associated alterations of the mitochondrial genome occur in several different species; however, their physiological relevance remains unclear.The age-associated changes of mitochondrial DNA (mtDNA) include nucleotide point mutations and modifications, as well as deletions.In this review, we summarize the current literature on age-associated mtDNA mutations and deletions and comment on their abundance.A clear need exists for a more thorough evaluation of the total damage to the mitochondrial genome that accumulates in aged tissues.᭧ 1997 Elsevier Science Inc."
            },
            {
                "document_id": "8a9fe1bc-7fa3-40ee-ade0-9a498bcf9def",
                "section_type": "main",
                "text": "Mitochondrial genetics\n\nOne underexplored avenue for determining maternal risk for preterm birth involves the influence of the mitochondrial genome.The high mutation rate of mito chondrial DNA (mtDNA), together with the fact that most of its encoded proteins are evolutionarily con served, allowing for the selection of neutral or beneficial variants, has generated interest in defining human mtDNA variations and their roles in human biology [58]."
            },
            {
                "document_id": "fd5edd5b-25d5-41ef-b9ad-7599905b844f",
                "section_type": "main",
                "text": "\n\nMitochondrial DNA (mtDNA) rearrangements have been shown to accumulate with age in the post-mitotic tissues of a variety of animals and have been hypothesized to result in the age-related decline of mitochondrial bioenergetics leading to tissue and organ failure.Caloric restriction in rodents has been shown to extend life span supporting an association between bioenergetics and senescence.In the present study, we use full length mtDNA amplification by long-extension polymerase chain reaction (LX-PCR) to demonstrate that mice accumulate a wide variety of mtDNA rearrangements with age in post mitotic tissues.Similarly, using an alternative PCR strategy, we have found that 2-4 kb minicircles containing the origin of heavy-strand replication accumulate with age in heart but not brain.Analysis of mtDNA structure and conformation by Southern blots of unrestricted DNA resolved by field inversion gel electrophoresis have revealed that the brain mtDNAs of young animals contain the traditional linear, nicked, and supercoiled mtDNAs while old animals accumulate substantial levels of a slower migrating species we designate age-specific mtDNAs.In old caloric restricted animals, a wide variety of rearranged mtDNAs can be detected by LX-PCR in post mitotic tissues, but Southern blots of unrestricted DNA reveals a marked reduction in the levels of the agespecific mtDNA species.These observations confirm that mtDNA mutations accumulate with age in mice and suggest that caloric restriction impedes this progress."
            },
            {
                "document_id": "2f39f55f-2604-49d4-9589-0e1403b84d7a",
                "section_type": "main",
                "text": "\n\nHowever, no studies have investigated whether the effects of age on the two mitochondrial characteristics are independent, as it is possible that age can affect mtDNA copy number through age-related heteroplasmy changes or vice versa.In this study, we demonstrated that age was independently associated with mtDNA copy number and heteroplasmy.Furthermore, compared to previous studies, we also included WBC count and platelet count as covariates in the regression model to adjust for potential bias caused by blood cell contaminations.Mitochondrial biogenesis has been proposed as a marker of many age-related health outcomes or even the aging process itself [58].Our results suggested that both mtDNA heteroplasmy and copy number should be included to establish this relationship.Mitochondrial mutations that occur early in life can clonally expand to cause mitochondrial dysfunction and further contribute to aging through a number of potential mechanisms including decreased oxidative capacity and energy production capacity, but also nuclear signaling and transcriptional dysregulation [59][60][61][62][63].In addition, decreased mtDNA copy number may also lead to decreased energy production and/or decreased mitochondrial gene expression [57,64].Maintaining both mtDNA quality and quantity together may help to counteract or slow down the aging process."
            },
            {
                "document_id": "1152aa3c-a9df-4745-b262-97c03ccf0e1a",
                "section_type": "main",
                "text": "\n\nWe next examined whether aging influenced behavior of the mice and added 6-month-old and 12-month-old mice to the experiments.The interaction between nDNA and mtDNA seemed to be more pronounced in older mice, as the difference in the slopes of the learning curves of H and H mtDNA N mice was amplified with age (Fig. 1c).Mitochondrial decay has been associated with memory loss and particularly with age-dependent cognitive impairment 4,7 . ).All effects were significant, including the double interaction of nDNA, mtDNA and age (P < .01).For all age groups, the transfer of mtDNA to the parental strains resulted in fewer steps taken. (c) Number of holes explored.All effects were significant including the double interaction (P < 0.0007), with congenic strains exploring fewer holes."
            },
            {
                "document_id": "fd5edd5b-25d5-41ef-b9ad-7599905b844f",
                "section_type": "abstract",
                "text": "\nMitochondrial DNA (mtDNA) rearrangements have been shown to accumulate with age in the post-mitotic tissues of a variety of animals and have been hypothesized to result in the age-related decline of mitochondrial bioenergetics leading to tissue and organ failure.Caloric restriction in rodents has been shown to extend life span supporting an association between bioenergetics and senescence.In the present study, we use full length mtDNA amplification by long-extension polymerase chain reaction (LX-PCR) to demonstrate that mice accumulate a wide variety of mtDNA rearrangements with age in post mitotic tissues.Similarly, using an alternative PCR strategy, we have found that 2-4 kb minicircles containing the origin of heavy-strand replication accumulate with age in heart but not brain.Analysis of mtDNA structure and conformation by Southern blots of unrestricted DNA resolved by field inversion gel electrophoresis have revealed that the brain mtDNAs of young animals contain the traditional linear, nicked, and supercoiled mtDNAs while old animals accumulate substantial levels of a slower migrating species we designate age-specific mtDNAs.In old caloric restricted animals, a wide variety of rearranged mtDNAs can be detected by LX-PCR in post mitotic tissues, but Southern blots of unrestricted DNA reveals a marked reduction in the levels of the agespecific mtDNA species.These observations confirm that mtDNA mutations accumulate with age in mice and suggest that caloric restriction impedes this progress."
            },
            {
                "document_id": "5d133558-fc58-42c7-8407-b3e734e8db9c",
                "section_type": "abstract",
                "text": "\nQuantitative information on the cell-to-cell distribution of all possible mitochondrial DNA (mtDNA) mutations in young and aged tissues is needed to assess the relevance of these mutations to the aging process.In the present study, we used PCR amplification of full-length mitochondrial genomes from single cells to scan human cardiomyocytes for all possible large deletions in mtDNA.Analysis of more than 350 individual cells that were derived from three middleaged and four centenarian donors demonstrates that while most of the cells contain no deletions, in certain cardiomyocytes a significant portion of the mtDNA molecules carried one particular deletion.Different affected cells contained different deletions.Although similar numbers of cells were screened for each donor, these deletion-rich cells were found only in the hearts of old donors, where they occurred at a frequency of up to one in seven cells.These initial observations demonstrate the efficiency of the method and indicate that mitochondrial mutations have the potential to play an important role in human myocardial aging."
            },
            {
                "document_id": "21d2cb60-92ab-4fbb-a3a1-85d3424881c1",
                "section_type": "main",
                "text": "\n\nAs a pacesetter for physiological processes, variation in metabolic rate can determine the shape of energetic trade-offs and thereby drive variation in life-history traits.In turn, such variation in metabolic performance and life-histories can have profound consequences for lifespan and lifetime fitness.Thus, the extent to which metabolic rate variation is due to phenotypic plasticity or fixed genetic differences among individuals or populations is likely to be shaped by natural selection.Here, we first present a generalized framework describing the central role of mitochondria in processes linking environmental, genomic, physiological, and aging variation.We then present a test of these relationships in an exemplary system: populations of garter snakes (Thamnophis elegans) exhibiting contrasting life-history strategiesfast-growing, early-reproducing, and fast-aging (FA) versus slow-growing, late-reproducing, and slow-aging (SA).Previous work has characterized divergences in mitochondrial function, reactive oxygen species processing, and whole-organism metabolic rate between these contrasting life-history ecotypes.Here, we report new data on cellular respiration and mitochondrial genomics and synthesize these results with previous work.We test hypotheses about the causes and implications of mitochondrial genome variation within this generalized framework.First, we demonstrate that snakes of the FA ecotype increase cellular metabolic rate across their lifespan, while the opposite pattern holds for SA snakes, implying that reduced energetic throughput is associated with a longer life.Second, we show that variants in mitochondrial genomes are segregating across the landscape in a manner suggesting selection on the physiological consequences of this variation in habitats varying in temperature, food availability, and rates of predation.Third, we demonstrate functional variation in whole-organism metabolic rate related to these mitochondrial genome sequence variants.With this synthesis of numerous datasets, we are able to further characterize how variation across levels of biological organization interact within this generalized framework and how this has resulted in the emergence of distinct life-history ecotypes that vary in their rates of aging and lifespan."
            },
            {
                "document_id": "fd5edd5b-25d5-41ef-b9ad-7599905b844f",
                "section_type": "main",
                "text": "\n\nIt was previously reported that no substantive changes accumulate in the structure of the mitochondrial genome with age in either fibroblasts or Drosophila melanogaster (17,18).This was determined through analysis by Southern blot of uniquely restricted mitochondrial DNA.However, recent studies have shown that complex mtDNA rearrangements associated with human disease (19)(20)(21) can be 'masked' through restriction digestion (22).In addition, Southern analysis of unrestricted mtDNAs from senescent human skeletal muscle has revealed the accumulation of additional mtDNA species not found in young tissues which migrate with the same mobility as deleted mtDNAs (10).Hence, detection of age-specific mtDNA rearrangements requires application of appropriate methodologies."
            },
            {
                "document_id": "2f39f55f-2604-49d4-9589-0e1403b84d7a",
                "section_type": "main",
                "text": "\n\nAging is commonly characterized as a time-dependent progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death [14].One important factor in aging is the accumulation of DNA damage over time [15].mtDNA has been considered a major target of aging-associated mutation accumulation, possibly because it experiences higher oxidative damages, more turnover, and has lower replication fidelity compared to nuclear DNA (nDNA) [16][17][18].Mice carrying elevated mtDNA mutation burden present premature signs of aging including hair loss, kyphosis, and premature death (lifespan shortened by up to 50%) [19,20].In human studies, mtDNA heteroplasmy incidence increases with age [21][22][23], while lower mtDNA copy number has been reported in aged populations [12,24].Ding et al. reported an trend of increased heteroplasmies and decreased mtDNA copy number with age in their study population [25].However, previous studies were limited in one or more ways: i) limited power in detecting low-to-medium frequency heteroplasmies in blood due to low sequencing depth; ii) relatively small sample sizes, limiting statistical power; iii) small age range; iv) whole blood as the source of DNA, which contains several sources of contaminants for mtDNA analysis; and/or v) assessing either mtDNA mutation or copy number, but not both in the same biological samples.Thus, it is largely unknown whether the impacts of age on mtDNA mutation burden and on copy number are independent from each other."
            },
            {
                "document_id": "b547b680-8602-4a15-8d91-6a6d3ffa19d2",
                "section_type": "main",
                "text": "\n\nIn the present study, myocardium was found to contain approximately twice the number of mtDNA genomes per diploid nucleus as skeletal muscle (6970 versus 3650, P = 0.006).This is in keeping with an earlier study (10) that used Southern hybridisation.This ®nding accords with a greater reliance on aerobic ATP production by the myocardium than by skeletal muscle.The mtDNA copy number in myocardium and skeletal muscle was found to remain unchanged over a 10 decade timespan in the tissues we studied (Figs 3 and 4), similar to the previous ®ndings on rat heart (12)."
            },
            {
                "document_id": "4f709611-ea0b-4bcc-a634-df5d518ccb54",
                "section_type": "main",
                "text": "\n\nAging is a complex process as a time-dependent progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death [74], and as we described above, aging is highly associated with mtDNA mutations; in fact heteroplasmy incidence increases with age, while lower mtDNA copy number has been reported in aged populations as well as mitochondria morphology, abundance, and oxidative phosphorylation activity [75,76].Interestingly, in aging the significant amount of these mutations converges in sites that encode structural subunits of the ETC such as complexes I and III [77], leading to OxPhos uncoupling and mitochondrial dysfunction in aged population.Since there are several limitations to study mitochondrial metabolism in human samples, in this section we briefly described the implications of mitochondrial metabolism for aging in the most studied and high energy demand human tissues, such as skeletal muscle, heart, and brain."
            },
            {
                "document_id": "ddc57e64-2b93-41e5-baac-6bdb52e7b6e6",
                "section_type": "main",
                "text": "\n\nIt is not known how mtDNA deletions accumulate during aging.Although the smaller size of partially-deleted molecules suggested early on that they could have a replicative advantage (5,6), direct evidence of this phenomenon has been lacking.In most cases, partially-deleted mtDNAs (DmtDNAs) contain the same number of replication origins as the wildtype genome but they can be up to 50% shorter (7).We have previously shown that cells harboring homoplasmic levels of DmtDNA repopulated their organelles with mtDNA faster than cells containing wild-type mitochondrial genomes (8).In these cells, however, there was no competition between mutated and wild-type genomes, as they were present in a homoplasmic state.Therefore, we could not rule out that differences in mtDNA repopulation were due to different metabolic states of these cells.In the present study, we addressed this issue by studying heteroplasmic cells.Our results showed that mtDNA with large deletions, but not with pathogenic point mutations, repopulates organelles signi®cantly faster than wild-type genomes in the same cell, particularly during relaxed copy number control."
            },
            {
                "document_id": "ddc57e64-2b93-41e5-baac-6bdb52e7b6e6",
                "section_type": "main",
                "text": "\n\nAlthough there may be important differences between postmitotic tissues and our culture cell system, the observation of heteroplasmy ¯uctuations during rapid mtDNA repopulation allows us to draw some conclusions regarding the molecular aspect of differential repopulation rates.Our results are in agreement with previous in situ hybridization experiments that showed that most age-related mtDNA deletions in muscle are caused by clonal expansion of deletions (36,37).In muscle, mitochondria with defective function are stimulated to proliferate, and that may increase mtDNA replication, mimicking a relaxed copy number control situation.It also strengthened the view that age-related mtDNA deletions are probably generated at random but their levels gradually increase with time.Our results also raise the possibility that the accumulation of DmtDNAs may be accelerated by metabolic or environmental changes leading to either a transient reduction in mtDNA levels or a relaxation in copy number control."
            },
            {
                "document_id": "2f39f55f-2604-49d4-9589-0e1403b84d7a",
                "section_type": "abstract",
                "text": "\nBackground: The accumulation of mitochondrial DNA (mtDNA) mutations, and the reduction of mtDNA copy number, both disrupt mitochondrial energetics, and may contribute to aging and age-associated phenotypes.However, there are few genetic and epidemiological studies on the spectra of blood mtDNA heteroplasmies, and the distribution of mtDNA copy numbers in different age groups and their impact on age-related phenotypes.In this work, we used whole-genome sequencing data of isolated peripheral blood mononuclear cells (PBMCs) from the UK10K project to investigate in parallel mtDNA heteroplasmy and copy number in 1511 women, between 17 and 85 years old, recruited in the TwinsUK cohorts.Results: We report a high prevalence of pathogenic mtDNA heteroplasmies in this population.We also find an increase in mtDNA heteroplasmies with age (β = 0.011, P = 5.77e-6), and showed that, on average, individuals aged 70-years or older had 58.5% more mtDNA heteroplasmies than those under 40-years old.Conversely, mtDNA copy number decreased by an average of 0.4 copies per year (β = −0.395,P = 0.0097).Multiple regression analyses also showed that age had independent effects on mtDNA copy number decrease and heteroplasmy accumulation.Finally, mtDNA copy number was positively associated with serum bicarbonate level (P = 4.46e-5), and inversely correlated with white blood cell count (P = 0.0006).Moreover, the aggregated heteroplasmy load was associated with blood apolipoprotein B level (P = 1.33e-5), linking the accumulation of mtDNA mutations to age-related physiological markers.Conclusions: Our population-based study indicates that both mtDNA quality and quantity are influenced by age.An open question for the future is whether interventions that would contribute to maintain optimal mtDNA copy number and prevent the expansion of heteroplasmy could promote healthy aging."
            },
            {
                "document_id": "4f010a74-a9b4-4538-94f7-ae8f35c8b96e",
                "section_type": "main",
                "text": "DNA genotype during development\n\nRelatively rapid turnover of mtDNA in cells was documented (129).The half-life of mtDNA was 6.7 days in heart, 9.4 days in liver, 10.4 days in kidney, and 31 days in brain in adult rats, while a half-life of heart nDNA was -30 days.Accompanying mtDNA turnover, replicative advantage either to mutant or to wild-type mitochondrial genome has been reported on the germline point mutations."
            },
            {
                "document_id": "63308275-a453-415d-8814-6f2932148ecd",
                "section_type": "main",
                "text": "\n\nIn this study, we have taken advantage of recent developments in high-throughput DNA sequencing to assemble one of the largest ancient mitochondrial DNA (mtDNA) datasets to date, consisting of a total of nearly 300,000 nucleotides of unique sequence data from 18 individual samples.By exploiting permafrost-preserved hair shaft material as a source of ancient DNA (3), we present five newly sequenced Siberian woolly mammoth mtDNA genomes (Fig. 1).In combination with the 13 previously published (3-7), these make it possible to scan for signs of natural selection along the mitochondrial genome and allow further investigation of the population structure discovered in past studies (1,8), including the inference of a more precise evolutionary time scale.Analysis of the combined dataset indicates a deep temporal split between the two clades (I and II).This observation, coupled with statistical analysis of the temporal distribution of the 14 C ages of these and previously identified members of the two mammoth clades (1), suggests that, although they are apparently sympatric, clade II vanished from Siberia long before clade I."
            },
            {
                "document_id": "21d2cb60-92ab-4fbb-a3a1-85d3424881c1",
                "section_type": "abstract",
                "text": "\nAs a pacesetter for physiological processes, variation in metabolic rate can determine the shape of energetic trade-offs and thereby drive variation in life-history traits.In turn, such variation in metabolic performance and life-histories can have profound consequences for lifespan and lifetime fitness.Thus, the extent to which metabolic rate variation is due to phenotypic plasticity or fixed genetic differences among individuals or populations is likely to be shaped by natural selection.Here, we first present a generalized framework describing the central role of mitochondria in processes linking environmental, genomic, physiological, and aging variation.We then present a test of these relationships in an exemplary system: populations of garter snakes (Thamnophis elegans) exhibiting contrasting life-history strategiesfast-growing, early-reproducing, and fast-aging (FA) versus slow-growing, late-reproducing, and slow-aging (SA).Previous work has characterized divergences in mitochondrial function, reactive oxygen species processing, and whole-organism metabolic rate between these contrasting life-history ecotypes.Here, we report new data on cellular respiration and mitochondrial genomics and synthesize these results with previous work.We test hypotheses about the causes and implications of mitochondrial genome variation within this generalized framework.First, we demonstrate that snakes of the FA ecotype increase cellular metabolic rate across their lifespan, while the opposite pattern holds for SA snakes, implying that reduced energetic throughput is associated with a longer life.Second, we show that variants in mitochondrial genomes are segregating across the landscape in a manner suggesting selection on the physiological consequences of this variation in habitats varying in temperature, food availability, and rates of predation.Third, we demonstrate functional variation in whole-organism metabolic rate related to these mitochondrial genome sequence variants.With this synthesis of numerous datasets, we are able to further characterize how variation across levels of biological organization interact within this generalized framework and how this has resulted in the emergence of distinct life-history ecotypes that vary in their rates of aging and lifespan. \"Sometimes reality is too complex.Stories give it form.\""
            },
            {
                "document_id": "aa942230-9a43-4b5f-90d9-96d364861a57",
                "section_type": "main",
                "text": "\n\nAll of these factors and numerous others are areas that influence our daily lives.Consequently, some individuals may wish to change their energetic phenotype by changing their mtDNA genotype.If some people will undergo surgery to change their appearance, there will certainly be some who will submit to mtDNA alterations to change their life style, appearance, and physical performance.For example, changing a single mtDNA nucleotide of a high performance athlete to increase mitochondrial ATP production through altered OXPHOS coupling could increase performance by several percent and mean the difference between Olympic immortality versus obscurity.Since such a change would be undetectable by any reasonable standard screening procedure.Why wouldn't a competitive athlete take advantage of such an opportunity?"
            },
            {
                "document_id": "4f010a74-a9b4-4538-94f7-ae8f35c8b96e",
                "section_type": "main",
                "text": "\n\nThese results strongly urged the researchers' attention on mtDNA mutations and, as a result, bridged over the distance between the biochemical findings and the molecular biology of mtDNA."
            }
        ],
        "document_id": "8CC70421A233A4B1F89A6701731F7017",
        "engine": "gpt-4",
        "first_load": false,
        "focus": "api",
        "keywords": [
            "mtDNA",
            "mitochondrial&DNA",
            "nuclear&DNA",
            "heredity",
            "haplogroups",
            "mitochondrial&genome",
            "oxidative&phosphorylation",
            "OXPHOS",
            "mutation&rate",
            "mitophagy"
        ],
        "metadata": [
            {
                "object": "Carriers of hemochromatosis gene HFE 845A and 187G alleles have significantly higher mitochondrial DNA mtDNA levels than noncarriers, but mtDNA declines among all individuals on study during 48 weeks on uninterrupted antiretroviral therapy ART. Increased cellular mtDNA content may represent a compensatory response to mitochondrial stress that is influenced by iron-loading HFE variants.",
                "predicate": "http://www.w3.org/2000/01/rdf-schema#comment",
                "subject": "ndd791caee50643ad90a986f563d2a0dab120751"
            },
            {
                "object": "We also assessed mitochondrial DNA mtDNA content, citrate synthase activity, oxidative lesions to protein and mtDNA i.e., carbonyls and the abundance of mtDNA4834 deletion, and the mitochondrial transcription factor A TFAM binding to specific mtDNA regions.",
                "predicate": "http://www.w3.org/2000/01/rdf-schema#comment",
                "subject": "ndd791caee50643ad90a986f563d2a0dab998500"
            },
            {
                "object": "Mitochondrial mtDNA haplogroups show an influence on serum levels of catalase among osteoarthritis patients. Carriers of mtDNA haplogroup J show higher serum levels than non-J carriers.",
                "predicate": "http://www.w3.org/2000/01/rdf-schema#comment",
                "subject": "ndd791caee50643ad90a986f563d2a0dab494822"
            },
            {
                "object": "We determined mitochondrial DNA mtDNA and ACTN3 genotypes in Finnish elite endurance n = 52 and sprint n = 89 athletes, and found that the frequencies of mtDNA haplogroups differed significantly between the two groups",
                "predicate": "http://www.w3.org/2000/01/rdf-schema#comment",
                "subject": "ndd791caee50643ad90a986f563d2a0dab1002772"
            },
            {
                "object": "In mutated HMI1 the wild-type mitochondrial DNA is fragmented and loss of the wild-type mitochondrial genome is caused by this fragmentation of the mitochondrial DNA.",
                "predicate": "http://www.w3.org/2000/01/rdf-schema#comment",
                "subject": "ndd791caee50643ad90a986f563d2a0dab396367"
            },
            {
                "object": "The T790M mutation rate was 8.4% in overall patients. The T790M mutation was more frequent in patients with brain metastasis 30.0% . We found that post-TKI tyrosine kinase inhibitors samples 42.8% were associated with a higher T790M mutation rate. Subgroup analysis showed that the duration of TKI therapy for 6 to 10 months 66.6% and >10 months 75.0% were also associated with higher T790M mutation rate.",
                "predicate": "http://www.w3.org/2000/01/rdf-schema#comment",
                "subject": "ndd791caee50643ad90a986f563d2a0dab878154"
            },
            {
                "object": "Study revealed that Irc3 - a dsDNA dependent ATPase of the Superfamily II- is essential for yeast mtDNA maintenance. irc3Delta mutant yeast cells accumulated double-stranded breaks in mtDNA and lose the wild-type mitochondrial genome in the course of a few generations of growth on glucose-containing media. These results demonstrate that Irc3 is a mitochondrial branch migration enzyme.",
                "predicate": "http://www.w3.org/2000/01/rdf-schema#comment",
                "subject": "ndd791caee50643ad90a986f563d2a0dab748584"
            },
            {
                "object": "human ClpX, a novel mtDNA regulator, maintains mtDNA nucleoid distribution through TFAM function as a chaperone rather than as a protease and its involvement in mtDNA segregation.",
                "predicate": "http://www.w3.org/2000/01/rdf-schema#comment",
                "subject": "ndd791caee50643ad90a986f563d2a0dab364328"
            },
            {
                "object": "Here, we identified the E3 ubiquitin ligase HUWE1 as a key inducing factor in AMBRA1-mediated mitophagy, a process that takes place independently of the main mitophagy receptors. Furthermore, we show that mitophagy function of AMBRA1 is post-translationally controlled, upon HUWE1 activity, by a positive phosphorylation on its serine 1014.",
                "predicate": "http://www.w3.org/2000/01/rdf-schema#comment",
                "subject": "ndd791caee50643ad90a986f563d2a0dab339502"
            },
            {
                "object": "MGME1-mediated mtDNA processing is essential for faithful mitochondrial genome replication and might be required for intramolecular recombination of mtDNA.",
                "predicate": "http://www.w3.org/2000/01/rdf-schema#comment",
                "subject": "ndd791caee50643ad90a986f563d2a0dab480937"
            }
        ],
        "question": "Describe the role of mitochondrial DNA in heredity and how it differs from nuclear DNA.",
        "subquestions": null,
        "task_id": "8CC70421A233A4B1F89A6701731F7017",
        "usage": {
            "chatgpt": 9175,
            "gpt-4": 5434,
            "gpt-4-turbo-preview": 4489
        },
        "user_id": 2
    },
    "document_id": "8CC70421A233A4B1F89A6701731F7017",
    "task_id": "8CC70421A233A4B1F89A6701731F7017"
}