DNA deletions and clonal mutations drive premature aging in mitochondrial mutator mice

Vermulst, Marc; Wanagat, Jonathan; Kujoth, Gregory C.; Bielas, Jason H.; Rabinovitch, Peter S.; Prolla, Tomas A.; Loeb, Lawrence A.

doi:10.1038/ng.95

Cited by 365 publications

(340 citation statements)

References 15 publications

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“…We found that heart, skeletal muscle, and duodenum tissues of 15-month-old rescued mnd2 mice contained many COX-negative cells ( COX-negative cells have also been described in brain tissues from premature aging mice. 36 However, we did not detect COX-negative cells in brain tissue sections of rescued mnd2 mice or their heterozygous mnd2/ þ ;Tg littermates (Supplementary Figure 4), demonstrating that the lack of HtrA2 activity is responsible for the COX deficiency in nonneuronal tissues.…”

Section: Loss Of Htra2 Results In Increased Mtdna Deletionsmentioning

confidence: 94%

“…These results indicate that HtrA2 deficiency in non-neuronal tissues causes increased clonally expanded mtDNA deletions, which are believed to be a major contributing factor leading to premature aging and decreased life span. 2,3,36 Loss of HtrA2 causes increased autophagosome activity. Increased autophagy has been observed in premature aging mice.…”

Section: Loss Of Htra2 Results In Increased Mtdna Deletionsmentioning

confidence: 99%

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Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging

et al. 2012

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mnd2 mice die prematurely as a result of neurodegeneration 30-40 days after birth due to loss of the enzymatic activity of the mitochondrial quality control protease HtrA2/Omi. Here, we show that transgenic expression of human HtrA2/Omi in the central nervous system of mnd2 mice rescues them from neurodegeneration and prevents their premature death. Interestingly, adult transgenic mnd2 mice develop accelerated aging phenotypes, such as premature weight loss, hair loss, reduced fertility, curvature of the spine, heart enlargement, increased autophagy, and death by 12-17 months of age. These mice also have elevated levels of clonally expanded mitochondrial DNA (mtDNA) deletions in their tissues. Our results provide direct genetic evidence linking mitochondrial protein quality control to mtDNA deletions and aging in mammals. Cell Death and Differentiation (2013) 20, 259-269; doi:10.1038/cdd.2012 published online 14 September 2012 Mitochondria are dynamic organelles primarily involved in the production of adenosine triphosphate (ATP) through oxidative phosphorylation. They also play important roles in diverse cellular processes such as cell death, autophagy and innate immunity. 1 As a consequence of oxidative phosphorylation, mitochondria produce reactive oxygen species (ROS), which damages mitochondrial proteins, lipids and nucleic acids, because of their proximity to the source of ROS production. Accumulation over time of mutations and deletions in mitochondrial DNA (mtDNA) together with increased protein misfolding, as a result of ROS damage, leads to ageassociated decline in mitochondrial function, which is believed to be responsible for organismal aging and age-associated diseases. [2][3][4] To maintain optimal mitochondrial function over time, a number of quality control mechanisms exist that monitor and regulate all aspects of mitochondrial physiology. Damaged and unfolded mitochondrial proteins are removed by mitochondrial quality control proteases, which recognize these proteins and degrade them. 5,6 The ATP-dependent AAA (ATPase-Associated with diverse cellular Activities) proteases, are among the best-characterized proteases implicated in mitochondrial protein quality control. 7 The AAA proteases, ClpXP and Lon, located in the matrix are involved in quality control of matrix proteins. Although no specific mitochondrial substrate has been identified for the ClpXP protease, in vitro studies showed that Lon protease preferentially targets oxidatively damaged matrix aconitase. 8 Two additional AAA proteases, Paraplegin (encoded by the SPG7 gene) and YME1L, are associated with the inner membrane with their catalytic sites facing the matrix and intermembrane space, respectively. 7 These proteases are believed to be primarily involved in the degradation of damaged and unfolded membrane proteins of the electron transport chain. In addition, Paraplegin has been shown to process the mitochondrial ribosomal protein MrpL32, 9 suggesting that it might also function in mitochondrial ribosome assembly. Loss-of-functi...

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Section: Loss Of Htra2 Results In Increased Mtdna Deletionsmentioning

confidence: 94%

Section: Loss Of Htra2 Results In Increased Mtdna Deletionsmentioning

confidence: 99%

Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging

et al. 2012

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“…First, it is possible that PolG and Tw + mice do not recapitulate the same mechanisms that accelerate or protect against loss of mitochondrial function seen in normal aging, respectively. In particular, the rate at which mtDNA mutations reach phenotypic expression differs markedly among tissues (Vermulst et al., 2008) and vessels might be protected from these manipulations. However, aging at/after 44 wk was associated with a marked reduction in mtCN and mitochondrial respiration, while Tw + mice maintained mtCN and respiration at 44 and 72 wk to levels seen in younger mice.…”

Section: Discussionmentioning

confidence: 99%

Restoring mitochondrial DNA copy number preserves mitochondrial function and delays vascular aging in mice

et al. 2018

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SummaryAging is the largest risk factor for cardiovascular disease, yet the molecular mechanisms underlying vascular aging remain unclear. Mitochondrial DNA (mtDNA) damage is linked to aging, but whether mtDNA damage or mitochondrial dysfunction is present and directly promotes vascular aging is unknown. Furthermore, mechanistic studies in mice are severely hampered by long study times and lack of sensitive, repeatable and reproducible parameters of arterial aging at standardized early time points. We examined the time course of multiple invasive and noninvasive arterial physiological parameters and structural changes of arterial aging in mice, how aging affects vessel mitochondrial function, and the effects of gain or loss of mitochondrial function on vascular aging. Vascular aging was first detected by 44 weeks (wk) of age, with reduced carotid compliance and distensibility, increased β‐stiffness index and increased aortic pulse wave velocity (PWV). Aortic collagen content and elastin breaks also increased at 44 wk. Arterial mtDNA copy number (mtCN) and the mtCN‐regulatory proteins TFAM, PGC1α and Twinkle were reduced by 44 wk, associated with reduced mitochondrial respiration. Overexpression of the mitochondrial helicase Twinkle (Tw+) increased mtCN and improved mitochondrial respiration in arteries, and delayed physiological and structural aging in all parameters studied. Conversely, mice with defective mitochondrial polymerase‐gamma (PolG) and reduced mtDNA integrity demonstrated accelerated vascular aging. Our study identifies multiple early and reproducible parameters for assessing vascular aging in mice. Arterial mitochondrial respiration reduces markedly with age, and reduced mtDNA integrity and mitochondrial function directly promote vascular aging.

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“…Ageing is a major risk factor for heart failure and mitochondrial dysfunction is also central to theories of ageing. Mitochondrial function and mitochondrial DNA (mtDNA) quality were shown to decline with age in postmitotic tissues [14][15][16][17] , and several recent studies, reporting on defects in mtDNA quality control mechanisms in mice, have shown that these mutant animals develop a phenotype of premature aging 17,18 . Given these findings, mitochondrial quality control may be associated with aging-related decreases in cardiac contractility and the pathogenesis of specific heart diseases that are especially caused by mitochondrial dysfunction including doxorubicin (DOX)-induced cardiotoxicity 19 .…”

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confidence: 99%

Cytosolic p53 inhibits Parkin-mediated mitophagy and promotes mitochondrial dysfunction in the mouse heart

et al. 2013

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Cumulative evidence indicates that mitochondrial dysfunction has a role in heart failure progression, but whether mitochondrial quality control mechanisms are involved in the development of cardiac dysfunction remains unclear. Here we show that cytosolic p53 impairs autophagic degradation of damaged mitochondria and facilitates mitochondrial dysfunction and heart failure in mice. Prevalence and induction of mitochondrial autophagy is attenuated by senescence or doxorubicin treatment in vitro and in vivo. We show that cytosolic p53 binds to Parkin and disturbs its translocation to damaged mitochondria and their subsequent clearance by mitophagy. p53-deficient mice show less decline of mitochondrial integrity and cardiac functional reserve with increasing age or after treatment with doxorubicin. Furthermore, overexpression of Parkin ameliorates the functional decline in aged hearts, and is accompanied by decreased senescence-associated b-galactosidase activity and proinflammatory phenotypes. Thus, p53-mediated inhibition of mitophagy modulates cardiac dysfunction, raising the possibility that therapeutic activation of mitophagy by inhibiting cytosolic p53 may ameliorate heart failure and symptoms of cardiac ageing.

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DNA deletions and clonal mutations drive premature aging in mitochondrial mutator mice

Cited by 365 publications

References 15 publications

Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging

Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging

Restoring mitochondrial DNA copy number preserves mitochondrial function and delays vascular aging in mice

Cytosolic p53 inhibits Parkin-mediated mitophagy and promotes mitochondrial dysfunction in the mouse heart

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