Mitochondrial DNA copy number is regulated in a tissue specific manner by DNA methylation of the nuclear-encoded DNA polymerase gamma A

Kelly, Richard; Mahmud, Arsalan; McKenzie, Matthew; Trounce, Ian A.; John, Justin C. St.

doi:10.1093/nar/gks770

Cited by 167 publications

(144 citation statements)

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“…These studies demonstrate the influence of the nucleus, whether through genetic or epigenetic means, on mtDNA segregation (Dunbar et al 1995) and tissue-specific regulation of mtDNA variants. As the variations in our mini-pig model were mainly restricted to highrespiratory tissues (brain, diaphragm, muscle, liver, heart, and fat), this suggests that there is epigenetic regulation of variant load to ensure the regulation of OXPHOS performance, which is reflected by higher mtDNA copy number (Kelly et al 2012;St John 2014). For example, for adipose tissue, this would link OXPHOS regulation to adipogenesis (Hofmann et al 2012), insulin metabolism (Ryu et al 2013), and thermogenesis (Duteil et al 2014).…”

Section: Discussionmentioning

confidence: 97%

“…Cells can regulate the replication of their mtDNA copy number to maintain a specific set point for biosynthesis of OXPHOS subunits, which, together with the nuclear-encoded subunits, support the production of ATP by the electron transport chain (Kelly et al 2012). Among the mini-pig samples, high-respiratory tissues showed lower variant load correlated with increased mtDNA copy number.…”

Section: Discussionmentioning

confidence: 99%

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Segregation of Naturally Occurring Mitochondrial DNA Variants in a Mini-Pig Model

et al. 2016

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The maternally inherited mitochondrial genome (mtDNA) is present in multimeric form within cells and harbors sequence variants (heteroplasmy). While a single mtDNA variant at high load can cause disease, naturally occurring variants likely persist at low levels across generations of healthy populations. To determine how naturally occurring variants are segregated and transmitted, we generated a mini-pig model, which originates from the same maternal ancestor. Following next-generation sequencing, we identified a series of low-level mtDNA variants in blood samples from the female founder and her daughters. Four variants, ranging from 3% to 20%, were selected for validation by high-resolution melting analysis in 12 tissues from 31 animals across three generations. All four variants were maintained in the offspring, but variant load fluctuated significantly across the generations in several tissues, with sexspecific differences in heart and liver. Moreover, variant load was persistently reduced in high-respiratory organs (heart, brain, diaphragm, and muscle), which correlated significantly with higher mtDNA copy number. However, oocytes showed increased heterogeneity in variant load, which correlated with increased mtDNA copy number during in vitro maturation. Altogether, these outcomes show that naturally occurring mtDNA variants segregate and are maintained in a tissue-specific manner across generations. This segregation likely involves the maintenance of selective mtDNA variants during organogenesis, which can be differentially regulated in oocytes and preimplantation embryos during maturation.KEYWORDS mitochondrial DNA; segregation; variants; generations; embryo W HILE the nuclear genome is inherited from both parents, the mitochondrial genome (mtDNA) is only inherited from the population present in the oocyte at fertilization (Chinnery et al. 2000). The porcine mitochondrial genome is 16.7 kb in size and encodes 13 of the subunits of the electron transport chain, which drives ATP synthesis through the biochemical process of oxidative phosphorylation (OXPHOS) (Ursing and Arnason 1998). It also encodes 22 transfer RNAs (tRNAs), which are interspersed between the encoding genes, and 2 ribosomal RNA (rRNA) complexes. mtDNA is located in the mitochondrial matrix and is tethered to proteins, which collectively form the mitochondrial nucleoid (Kucej and Butow 2007). mtDNA is present in multiple copies within cells and these genomes can be polymorphic. Consequently, cells can inherently harbor variant and wild-type (WT) sequences, i.e., heteroplasmic populations, of mtDNA at different frequencies (Wallace and Chalkia 2013).Most mtDNA variants are nonpathogenic (Ramos et al. 2013) but specific nucleotide mutations and large-scale deletions can lead to molecular defects, resulting in a wide range of clinical conditions, known as mitochondrial diseases (McFarland et al. 2007). Within the spectrum of mitochondrial diseases, the onset of symptoms can vary according to Copyright © 2016 Apart from the occurrence o...

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Segregation of Naturally Occurring Mitochondrial DNA Variants in a Mini-Pig Model

et al. 2016

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“…The median fractional concentration of plasma mitochondrial DNA was only 0.00045% in healthy subjects. This fractional concentration is relatively low, considering that the size of mitochondrial genome is 0.00053% of the size of the nuclear genome and there are 50-4,000 mitochondria per cell (46,47). The smaller size distribution and relatively low abundance of circulating mitochondrial DNA is likely to be due to the higher susceptibility of mitochondrial DNA to degradation due to the absence of histone protection.…”

Section: Discussionmentioning

confidence: 99%

Lengthening and shortening of plasma DNA in hepatocellular carcinoma patients

Jiang

Chan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

599

522

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The analysis of tumor-derived circulating cell-free DNA opens up new possibilities for performing liquid biopsies for the assessment of solid tumors. Although its clinical potential has been increasingly recognized, many aspects of the biological characteristics of tumor-derived cell-free DNA remain unclear. With respect to the size profile of such plasma DNA molecules, a number of studies reported the finding of increased integrity of tumor-derived plasma DNA, whereas others found evidence to suggest that plasma DNA molecules released by tumors might be shorter. Here, we performed a detailed analysis of the size profiles of plasma DNA in 90 patients with hepatocellular carcinoma, 67 with chronic hepatitis B, 36 with hepatitis B-associated cirrhosis, and 32 healthy controls. We used massively parallel sequencing to achieve plasma DNA size measurement at single-base resolution and in a genome-wide manner. Tumor-derived plasma DNA molecules were further identified with the use of chromosome arm-level z-score analysis (CAZA), which facilitated the studying of their specific size profiles. We showed that populations of aberrantly short and long DNA molecules existed in the plasma of patients with hepatocellular carcinoma. The short ones preferentially carried the tumor-associated copy number aberrations. We further showed that there were elevated amounts of plasma mitochondrial DNA in the plasma of hepatocellular carcinoma patients. Such molecules were much shorter than the nuclear DNA in plasma. These results have improved our understanding of the size profile of tumor-derived circulating cell-free DNA and might further enhance our ability to use plasma DNA as a molecular diagnostic tool.tumor markers | circulating tumor DNA | liquid biopsy | massively parallel sequencing | mitochondrial DNA A nalysis of circulating cell-free DNA has been increasingly used for the detection and monitoring of cancers (1-5). Different cancer-associated molecular characteristics, including copy number aberrations (6-9), methylation changes (10-13), single-nucleotide mutations (6, 14-17), cancer-derived viral sequences (18,19), and chromosomal rearrangements (20, 21), can be detected in the plasma of patients with various types of cancers. Despite the rapid expansion of clinical applications, many fundamental molecular characteristics of circulating DNA in cancer patients remain unclear. In particular, previous studies on the size of circulating DNA in cancer patients gave inconsistent results. Studies have demonstrated that the overall integrity of circulating DNA would increase in cancer patients compared with subjects without a malignant condition (22-25). Using PCR with different amplicon sizes, it was shown that the proportion of longer DNA would be higher in cancer patients. This aberration in DNA integrity was shown to be reversible after treatment, and the persistence of such changes was associated with poor prognosis (22, 26). On the other hand, there is also seemingly contradictory evidence that circulating DNA derived from t...

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“…Postfertilization, oocyte-derived mitochondria are segregated into each embryonic daughter cell until the blastocyst stage, at which point the pluripotent ICM cells establish a threshold mtDNA set point from which they commence mtDNA replication in a differentiation-specified manner (37,78). Because oocyte-derived mitochondria give rise to the entire complement of mitochondria in offspring tissues, their transmission, replication, and inheritance are tightly regulated; however, this process is sensitive to maternal metabolic status and stress such as obesity (37,78). Similar to what we found in a genetic mouse model of female obesity (88), we found that mtDNA copy number was reduced in fetal livers of female and male offspring from maternal HFD exposure, with levels not being further reduced by the addition of paternal obesity.…”

Section: Alterations To Fetal Health From Combined Paternal and Matermentioning

confidence: 99%

When two obese parents are worse than one! Impacts on embryo and fetal development

McPherson

Bell

Zander-Fox

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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McPherson NO, Bell VG, Zander-Fox DL, Fullston T, Wu LL, Robker RL, Lane M. When two obese parents are worse than one! Impacts on embryo and fetal development. Am J Physiol Endocrinol Metab 309: E568 -E581, 2015. First published July 21, 2015; doi:10.1152/ajpendo.00230.2015.-The prevalence of overweight and obesity in reproductive-age adults is increasing worldwide. While the effects of either paternal or maternal obesity on gamete health and subsequent fertility and pregnancy have been reported independently, the combination of having both parents overweight/ obese on fecundity and offspring health has received minimal attention. Using a 2 ϫ 2 study design in rodents we established the relative contributions of paternal and maternal obesity on fetal and embryo development and whether combined paternal and maternal obesity had an additive effect. Here, we show that parental obesity reduces fetal and placental weights without altering pregnancy establishment and is not dependent on an in utero exposure to a high-fat diet. Interestingly combined parental obesity seemed to accumulate both the negative influences of paternal and maternal obesity had alone on embryo and fetal health rather than an amplification, manifested as reduced embryo developmental competency, reduced blastocyst cell numbers, impaired mitochondrial function, and alterations to active and repressive embryonic chromatin marks, resulting in aberrant placental gene expression and reduced fetal liver mtDNA copy numbers. Further understanding both the maternal cytoplasmic and paternal genetic interactions during this early developmental time frame will be vital for understanding how developmental programming is regulated and for the proposition of interventions to mitigate their effects. blastocyst; oocyte; sperm; embryo; fertility; infertility; obesity THE PREVALENCE OF OVERWEIGHT and obesity in reproductive-age adults is increasing worldwide (62). For example, in America it is estimated that 70.9% of males and 61.9% of women are classified as overweight/obese (62). The comorbidities associated with obesity have been well defined; however, until recently the impact on pregnancy and fetal development has been less recognized. Although the effects of either paternal or maternal obesity on gamete health and subsequent fertility and pregnancy have been reported independently, the combination of having both parents overweight/obese on fecundity and offspring health has received minimal attention. This information is essential, as the percentage of couples of reproductive age with both partners overweight/ obese is increasing and is the predominant situation in many countries (62).To date, there have only been three studies that have assessed the combined effects of maternal and paternal obesity on pregnancy and fetal health, two in human-assisted reproductive technology (ART) cohorts and one using a rodent high-fat diet model (41,67,76). These studies found no effect of maternal and paternal obesity on pregnancy establishment (41, 67, 76); however, when ...

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Mitochondrial DNA copy number is regulated in a tissue specific manner by DNA methylation of the nuclear-encoded DNA polymerase gamma A

Cited by 167 publications

References 72 publications

Segregation of Naturally Occurring Mitochondrial DNA Variants in a Mini-Pig Model

Segregation of Naturally Occurring Mitochondrial DNA Variants in a Mini-Pig Model

Lengthening and shortening of plasma DNA in hepatocellular carcinoma patients

When two obese parents are worse than one! Impacts on embryo and fetal development

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