The Maintenance of Mitochondrial DNA Integrity--Critical Analysis and Update

Alexeyev, Mikhail; Shokolenko, Inna; Wilson, Glenn L.; LeDoux, Susan P.

doi:10.1101/cshperspect.a012641

Cited by 352 publications

(334 citation statements)

References 176 publications

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“…Mitochondria are unique because of their autonomous DNA (mtDNA), which encodes for proteins required for ATP synthesis. Therefore maintenance of mtDNA is important for normal mitochondrial function and for the diversity of mitochondrial genome [2]. Mitochondria form elongated tubules that continually divide and fuse to form a complex, interconnected and highly dynamic network inside of cells.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Mitochondrial Dynamics by Proteolytic Processing and Protein Turnover

Ali

McStay

2017

Preprint

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The mitochondrial network is a dynamic organization within eukaryotic cells that participates in a variety of essential cellular processes, such as ATP synthesis, central metabolism, apoptosis and inflammation. The mitochondrial network is balanced between rates of fusion and fission that respond to pathophysiologic signals to coordinate appropriate mitochondrial processes. Mitochondrial fusion and fission are regulated by proteins that either reside or translocate to the inner or outer mitochondrial membranes or are soluble in the inter-membrane space. Mitochondrial fission and fusion are performed by GTPases on the outer and inner mitochondrial membranes with the assistance of other mitochondrial proteins. Due to the essential nature of mitochondrial function for cellular homeostasis regulation of mitochondrial dynamics is under strict control. Some of the mechanisms used to regulate the function of these proteins are post-translational proteolysis and/or turnover and this review will discuss these mechanisms required for correct mitochondrial network organization. IntroductionMitochondria are the power houses of every nucleated cell, generating chemical energy in the form of adenosine triphosphate (ATP) by the oxidative phosphorylation (OXPHOS) system. Mitochondria are also important for the normal functioning of the cells as they regulate several crucial activities like differentiation, cell cycle, intracellular signaling and cell death [1]. Mitochondria are unique because of their autonomous DNA (mtDNA), which encodes for proteins required for ATP synthesis. Therefore maintenance of mtDNA is important for normal mitochondrial function and for the diversity of mitochondrial genome [2]. Mitochondria form elongated tubules that continually divide and fuse to form a complex, interconnected and highly dynamic network inside of cells. These dynamics processes not only regulate mitochondrial function but also mitochondrial shape, content exchange and mitochondrial communication with the cytoskeleton [3]. Due to the involvement of mitochondria in a large spectrum of cellular functions, these organelles play a key role in mediating cellular homeostasis. As a result a healthy population of mitochondria is critical for cell survival.

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Section: Introductionmentioning

confidence: 99%

Regulation of Mitochondrial Dynamics by Proteolytic Processing and Protein Turnover

Ali

McStay

2017

Preprint

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“…MtDNA is partially associated with the inner mitochondrial membrane, where the respiratory complexes catalyze oxidative phosphorylation and generate high levels of ROS which causes mtDNA damage [14][15][16]. Oxidative mtDNA damage can be repaired by both short-patch BER and long-patch BER [17][18][19], and UNG1 is involved in the repair process [20][21][22]. In addition to mtDNA, proteins responsible for mtDNA BER may also be a target of the high level of ROS since they are associated with the inner mitochondrial membrane where the respiratory complexes reside [23].…”

Section: Introductionmentioning

confidence: 99%

Hydrogen peroxide mediated mitochondrial UNG1-PRDX3 interaction and UNG1 degradation

Liu

Gong

et al. 2016

Free Radical Biology and Medicine

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“…We considered the possibility that high de novo mutation rate and fast turnover might allow mtDNA deletions to expand to physiologically significant levels even over the short lifespan of C. elegans . De novo point mutation rate is related to fidelity of the DNA polymerases and the extent of oxidative damage in the template DNA (Alexeyev et al, 2013). The rate of occurrence of mtDNA deletions in vivo is unknown, but the rate of occurrence of the frequently observed human mtDNA “common deletion” has been estimated to be 5.95 × 10 −8 per mtDNA replication in cell culture (Shenkar et al, 1996).…”

Section: Resultsmentioning

confidence: 99%

“…Oxidative damage is removed in mtDNA both through specific DNA damage repair systems as well as by degradation and resynthesis (turnover) of mtDNA molecules. UV lesions, unlike oxidative damage, are not enzymatically repaired within mtDNA because mitochondria lack nucleotide excision repair required for repairing UV‐induced damage (Alexeyev et al, 2013). Similarly, ethidium bromide (EtBr) intercalation cannot be repaired by the mtDNA repair machinery (Rooney et al, 2014).…”

Section: Resultsmentioning

confidence: 99%

“…The copy number of mtDNA per animal declines with age, with aged nematodes containing almost 30% fewer mtDNA compared to young adults (Gruber et al, 2011). Errors during mtDNA replication or during repair of DNA damage can result in mtDNA mutations, including large deletions spanning multiple mtDNA genes (Alexeyev, Shokolenko, Wilson, & LeDoux, 2013; Krishnan et al, 2008). Mutant mtDNA molecules can be amplified during normal mtDNA maintenance, creating additional copies of the mutant sequence within the same cell (Stewart & Chinnery, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Clonal expansion of mitochondrial DNA deletions is a private mechanism of aging in long‐lived animals

Lakshmanan

Yee

et al. 2018

Aging Cell

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Disruption of mitochondrial metabolism and loss of mitochondrial DNA (mtDNA) integrity are widely considered as evolutionarily conserved (public) mechanisms of aging (López‐Otín et al., Cell, 153, 2013 and 1194). Human aging is associated with loss in skeletal muscle mass and function (Sarcopenia), contributing significantly to morbidity and mortality. Muscle aging is associated with loss of mtDNA integrity. In humans, clonally expanded mtDNA deletions colocalize with sites of fiber breakage and atrophy in skeletal muscle. mtDNA deletions may therefore play an important, possibly causal role in sarcopenia. The nematode Caenorhabditis elegans also exhibits age‐dependent decline in mitochondrial function and a form of sarcopenia. However, it is unclear if mtDNA deletions play a role in C. elegans aging. Here, we report identification of 266 novel mtDNA deletions in aging nematodes. Analysis of the mtDNA mutation spectrum and quantification of mutation burden indicates that (a) mtDNA deletions in nematode are extremely rare, (b) there is no significant age‐dependent increase in mtDNA deletions, and (c) there is little evidence for clonal expansion driving mtDNA deletion dynamics. Thus, mtDNA deletions are unlikely to drive the age‐dependent functional decline commonly observed in C. elegans. Computational modeling of mtDNA dynamics in C. elegans indicates that the lifespan of short‐lived animals such as C. elegans is likely too short to allow for significant clonal expansion of mtDNA deletions. Together, these findings suggest that clonal expansion of mtDNA deletions is likely a private mechanism of aging predominantly relevant in long‐lived animals such as humans and rhesus monkey and possibly in rodents.

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The Maintenance of Mitochondrial DNA Integrity--Critical Analysis and Update

Cited by 352 publications

References 176 publications

Regulation of Mitochondrial Dynamics by Proteolytic Processing and Protein Turnover

Regulation of Mitochondrial Dynamics by Proteolytic Processing and Protein Turnover

Hydrogen peroxide mediated mitochondrial UNG1-PRDX3 interaction and UNG1 degradation

Clonal expansion of mitochondrial DNA deletions is a private mechanism of aging in long‐lived animals

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