Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons

Kraytsberg, Yevgenya; Kudryavtseva, Elena; McKee, Ann C.; Geula, Changiz; Kowall, Neil W.; Khrapko, Konstantin

doi:10.1038/ng1778

Cited by 794 publications

(656 citation statements)

References 14 publications

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“…These are plasma membrane NADPH oxidases that are highly expressed in astrocytes and oligodendrocytes (44,45), cytochromes P450 (46), and even catecholamine derivatives (47). Thus, elevated rates of basal ROS production by catecholamine metabolism might explain the high loads of mtDNA deletions observed in aged substatia nigra neurons (48,49). Additionally, oligodendrocytes and astrocytes contain considerable amounts of peroxisomes, which potentially also could contribute to overall physiological ROS production in brain tissue.…”

Section: Mitochondrial Formation Of Ros and Neurodegenerationmentioning

confidence: 99%

“…However, investigations of mtDNA alterations at the single cell level suggested that, beside mutagenesis, another process is equally relevant in the process of mutation accumulation: replicative segregation of mutated molecules. Single respiratory deficient neurons in substantia nigra of patients with PD display high amounts of single mtDNA deletion species, and different neurons are carrying different deletion species (48,49). This suggests that the critical mass of mutated mtDNA molecules within a cell is reached not by repeated mutagenesis but mainly through the clonal expansion of a few mutated molecules.…”

Section: Genetic Mechanisms Explaining Disease Progressionmentioning

confidence: 99%

“…In neurons, which cannot compensate easily the lacking ATP supply of oxidative phosphorylation by glycolysis, it appears more likely that mitochondria with high loads of pathogenic mutations approach a state of decreased membrane potential making them potential targets for quality control on the organelle level. Nevertheless, mitochondria containing high loads of mtDNA mutations tend also to accumulate in certain neurons (49), which might indicate some limitations in the operation of the mitochondrial quality control system.…”

Section: Genetic Mechanisms Explaining Disease Progressionmentioning

confidence: 99%

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Mitochondrial involvement in neurodegenerative diseases

Kunz

2013

IUBMB Life

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The classical bioenergetical view of the involvement of mitochondria in neurogeneration is based on the fact that mitochondria are the central players of ATP synthesis in neurons and their failure leads to neuronal dysfunction and eventually to cell death. Mutations in at least 39 genes in inherited neurodegenerative disorders seem to alter directly or indirectly mitochondrial function. Most of these mutations do not directly affect oxidative phosphorylation, but act through disturbed mitochondrial dynamics and quality control. This, however, does not invalidate the bioenergetic hypothesis.Neurodegeneration is not necessarily associated with a gross failure of ATP production, but might rather be a consequence of local insufficiencies of ATP supply in critical compartments of neurons, like the presynaptic terminal. We hypothesize that slow disease progression, at least in a subgroup of neurodegenerative diseases, can be explained by the parallel action of subcellular ATP insufficiency and clonal expansion of somatic mitochondrial DNA mutations, and particularly deletions. V C 2013 IUBMB Life, 65(3): [263][264][265][266][267][268][269][270][271][272] 2013

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Section: Mitochondrial Formation Of Ros and Neurodegenerationmentioning

confidence: 99%

Section: Genetic Mechanisms Explaining Disease Progressionmentioning

confidence: 99%

Section: Genetic Mechanisms Explaining Disease Progressionmentioning

confidence: 99%

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Mitochondrial involvement in neurodegenerative diseases

Kunz

2013

IUBMB Life

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“…Interestingly, the primary risk factor for PD development is ageing, which is itself correlated with the presence of CIV‐deficient neurons at similar levels to patients with IPD,6, 7 suggesting that age‐related damage accumulation could contribute to neuronal demise in IPD 6, 7…”

mentioning

confidence: 99%

Mitochondrial DNA Depletion in Respiratory Chain–Deficient Parkinson Disease Neurons

Grünewald

Rygiel

Hepplewhite

et al. 2016

Annals of Neurology

192

151

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ObjectiveTo determine the extent of respiratory chain abnormalities and investigate the contribution of mtDNA to the loss of respiratory chain complexes (CI–IV) in the substantia nigra (SN) of idiopathic Parkinson disease (IPD) patients at the single‐neuron level.MethodsMultiple‐label immunofluorescence was applied to postmortem sections of 10 IPD patients and 10 controls to quantify the abundance of CI–IV subunits (NDUFB8 or NDUFA13, SDHA, UQCRC2, and COXI) and mitochondrial transcription factors (TFAM and TFB2M) relative to mitochondrial mass (porin and GRP75) in dopaminergic neurons. To assess the involvement of mtDNA in respiratory chain deficiency in IPD, SN neurons, isolated with laser‐capture microdissection, were assayed for mtDNA deletions, copy number, and presence of transcription/replication‐associated 7S DNA employing a triplex real‐time polymerase chain reaction (PCR) assay.ResultsWhereas mitochondrial mass was unchanged in single SN neurons from IPD patients, we observed a significant reduction in the abundances of CI and II subunits. At the single‐cell level, CI and II deficiencies were correlated in patients. The CI deficiency concomitantly occurred with low abundances of the mtDNA transcription factors TFAM and TFB2M, which also initiate transcription‐primed mtDNA replication. Consistent with this, real‐time PCR analysis revealed fewer transcription/replication‐associated mtDNA molecules and an overall reduction in mtDNA copy number in patients. This effect was more pronounced in single IPD neurons with severe CI deficiency.InterpretationRespiratory chain dysfunction in IPD neurons not only involves CI, but also extends to CII. These deficiencies are possibly a consequence of the interplay between nDNA and mtDNA‐encoded factors mechanistically connected via TFAM. ANN NEUROL 2016;79:366–378

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“…Moreover, according to one study, even in muscle of a 92‐year‐old individual, less than 1% of skeletal muscle fibers exhibited electron transport chain abnormalities and clonally expanded mtDNA deletions (Bua et al, 2006). For clonal expansion to significantly impact the 302 neurons or 187 muscle cells of an average adult C. elegans , let alone to explain the general decline in metabolic rate seen in aging nematodes (Braeckman et al, 2002; Gruber et al, 2011; Yasuda et al, 2006), the fraction of affected cells would have to far exceed the level seen even in the oldest humans (up to 30% of neurons) (Itoh, Weis, Mehraein, & Müller‐Höcker, 1996; Kraytsberg et al, 2006). For clonal expansion to impact a significant fraction of nematode cells, we would have to assume mtDNA half‐life values far shorter than even the most rapid mtDNA turnover rate previously suggested for any animal.…”

Section: Discussionmentioning

confidence: 99%

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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Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons

Cited by 794 publications

References 14 publications

Mitochondrial involvement in neurodegenerative diseases

Mitochondrial involvement in neurodegenerative diseases

Mitochondrial DNA Depletion in Respiratory Chain–Deficient Parkinson Disease Neurons

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

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