Mitochondrial DNA alterations and reduced mitochondrial function in aging

Hebert, Sadie L.; Lanza, Ian R.; Nair, K. Sreekumaran

doi:10.1016/j.mad.2010.03.007

Cited by 80 publications

(75 citation statements)

References 129 publications

(180 reference statements)

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“…We identified and quantified the complexes in Coomassiestained native gels and could show a reduced mitochondrial protein content upon aging. Other parameters of mitochondrial function include the measurement of the rate of oxygen consumption in isolated mitochondria (Hebert et al, 2010). We found that complex I and complex II-dependent respiration in isolated mitochondria was decreased with age, suggesting age-related impairment of mitochondrial function.…”

Section: Discussionmentioning

confidence: 75%

“…Mitochondria have been suggested for decades to be implicated in aging (Harman, 1972), and it has been observed in a variety of organisms and tissues that mitochondrial function declines with age (Navarro & Boveris, 2004;Marcinek et al, 2005;Hebert et al, 2010). In humans, age-related mitochondrial dysfunction has been most often described in skeletal muscle tissue (Boffoli et al, 1994;Short et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial DNA copy number and function decrease with age in the short‐lived fish Nothobranchius furzeri

et al. 2011

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SummaryAmong vertebrates that can be kept in captivity, the annual fish Nothobranchius furzeri possesses the shortest known lifespan. It also shows typical signs of aging and is therefore an ideal model to assess the role of different physiological and environmental parameters on aging and lifespan determination. Here, we used Nothobranchius furzeri to study whether aging is associated with mitochondrial DNA (mtDNA) alterations and changes in mitochondrial function. We sequenced the complete mitochondrial genome of N. furzeri and found an extended control region. Large-scale mtDNA deletions have been frequently described to accumulate in other organisms with age, but there was no evidence for the presence of detectable age-related mtDNA deletions in N. furzeri. However, mtDNA copy number significantly decreased with age in skeletal muscle, brain, liver, skin and dorsal fin. Consistent with this finding, expression of Pgc-1a that encodes a transcriptional coactivator of mitochondrial biogenesis and expression of Tfam and mtSsbp both encoding mtDNA binding factors was downregulated with age. The investigation of possible changes in mitochondrial function revealed that the content of respiratory chain complexes III and IV was reduced in skeletal muscle with age. In addition, ADP-stimulated and succinate-dependent respiration was decreased in mitochondria of old fish. These findings suggest that despite the short lifespan, aging in N. furzeri is associated with a decline in mtDNA copy number, the downregulation of mtDNA-associated genes and an impairment of mitochondrial function.

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Section: Discussionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Mitochondrial DNA copy number and function decrease with age in the short‐lived fish Nothobranchius furzeri

et al. 2011

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“…This decrease in MRC functions may be caused by mutations in mitochondrial genes (Byrne et al, 1991;Hebert et al, 2010). Indeed, cytochrome oxidase has been observed to alter polypeptide patterns during ageing (Boffoli et al, 1994).…”

Section: Reversible Function Of Mitochondrial Genes During Buddingmentioning

confidence: 99%

“…At the organelle level, senescence accompanies the decrease in mitochondrial respiratory chain (MRC) activity (Byrne et al, 1991). It has been confirmed that one of the main causes of such functional deterioration in mitochondria is the time-related accumulation of DNA damage (Hebert et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Molecular anatomy of tunicate senescence: reversible function of mitochondrial and nuclear genes associated with budding cycles

et al. 2012

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SUMMARYZooids of the asexual strain of Polyandrocarpa misakiensis have a lifespan of 4-5 months; before dying, they produce many buds, enabling continuation of the strain. This study was designed to investigate the nature of gene inactivation and reactivation during this continuous process of senescence and budding. During senescence, the zooidal epidermis showed acid -galactosidase activity, lost proliferating cell nuclear antigen immunoreactivity and became ultrastructurally worn, indicating that the epidermis is a major tissue affected by the ageing process. Semi-quantitative PCR analysis showed that the genes encoding mitochondrial respiratory chains (MRCs) engaged in decreased transcriptional activity in senescent adults compared with younger adults. The results of in situ hybridization showed that the epidermis dramatically attenuates MRC expression during ageing but restores gene activity when budding commences. During budding and ageing, the nuclear gene Eed (a polycomb group component) was activated and inactivated in a pattern similar to that observed in MRCs. In buds, RNA interference (RNAi) of Eed attenuated Eed transcripts but did not affect the gene expression of pre-activated MRCs. A tunicate humoral factor, TC14-3, could induce Eed, accompanying the reactivation of MRC in adult zooids. When RNAi of Eed and Eed induction were performed simultaneously, zooidal cells and tissues failed to engage in MRC reactivation, indicating the involvement of Eed in MRC activation. Results of this study provide evidence that the mitochondrial gene activities of Polyandrocarpa can be reversed during senescence and budding, suggesting that they are regulated by nuclear polycomb group genes.

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“…The oxidation of proteins can inactivate and target them for degradation; oxidative damage to DNA causes single and double strand-breaks, crosslink to other molecules and base modifications, while lipid oxidation can generate membrane disturbances. As described above, mtDNA represents a critical target of oxidative damage since it does not contain histones and it is located in proximity to the production site of ROS (Hebert, Lanza et al, 2010). Once damaged, mtDNA can indirectly amplify oxidative stress since transcription of critical mitochondrial proteins is defective, leading to a vicious cycle of ROS production and eventually triggering cell death.…”

Section: Oxidative Phosphorylation and Energy Productionmentioning

confidence: 99%