Mitochondrial DNA Mutations, Oxidative Stress, and Apoptosis in Mammalian Aging

Kujoth, Gregory C.; Hiona, Asimina; Pugh, Thomas D.; Someya, Shinichi; Panzer, Karin; Wohlgemuth, Stephanie E.; Hofer, Tim; Seo, Arnold Y.; Sullivan, Rachel; Jobling, Wendy A.; Morrow, Jason D.; Remmen, Holly Van; Sedivy, John M.; Yamasoba, Tatsuya; Tanokura, Masaru; Weindruch, Richard; Leeuwenburgh, Christiaan; Prolla, Tomas A.

doi:10.1126/science.1112125

Cited by 1,858 publications

(1,795 citation statements)

References 22 publications

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“…The equivalent mutation, mtDNA4,977, deletion in human has also been identified, using archived temporal bones from patients with presbycusis [60][61][62]. Interestingly, consistent with a causal role for mtDNA mutations in ARHL, mice carrying a mutation in the exonuclease domain of the nucleus-encoded catalytic subunit of the mtDNA polymerase gamma (POLG), accumulated mtDNA mutations and displayed premature onset of ageingrelated phenotypes, including HL [63].…”

Section: Oxidative Stressmentioning

confidence: 99%

Ageing and hearing loss

Yan

2007

The Journal of Pathology

259

178

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Although many adults retain good hearing as they age, hearing loss associated with ageing is common among elderly persons. There are a number of pathophysiolological processes underlying age-related changes to functional components in the inner ear. Genetic factors determine the ageing process but are under the influence of intrinsic and environmental factors. It is difficult to distinguish changes of normal ageing from those of other contributing factors. The effects of age-related deafness can have significant physical, functional and mental health consequences. Although a deficit in hearing can be corrected to some degree by a hearing aid or other appropriate amplification devices, hearing-related rehabilitative needs are much more than simply amplifying external sound. Only by better understanding the process of ageing and its effect on the auditory function can we better accommodate elderly people in our day-to-day interactions. We review here the structure and function of the inner ear, pathophysiology associated with age-related hearing loss (ARHL), heritability, allelism and modifier genes of ARHL, and evaluate the genetic analyses for identification of genetic factors that are involved.

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Section: Oxidative Stressmentioning

confidence: 99%

Ageing and hearing loss

Yan

2007

The Journal of Pathology

259

178

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“…On the one hand, it is conceivable that the metabolic alterations and MOMP inhibition are acquired independently. In this scenario, mutations of mitochondrial DNA would increase the likelihood of cancer cells to undergo apoptosis (Kujoth et al, 2005), and only cells in which the apoptotic pathways are suppressed might be fit enough to participate in oncogenesis. On the other hand, the Warburg phenomenon could be mechanistically linked to MOMP inhibition.…”

Section: Introductionmentioning

confidence: 99%

Mitochondria as therapeutic targets for cancer chemotherapy

et al. 2006

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Mitochondria are vital for cellular bioenergetics and play a central role in determining the point-of-no-return of the apoptotic process. As a consequence, mitochondria exert a dual function in carcinogenesis. Cancer-associated changes in cellular metabolism (the Warburg effect) influence mitochondrial function, and the invalidation of apoptosis is linked to an inhibition of mitochondrial outer membrane permeabilization (MOMP). On theoretical grounds, it is tempting to develop specific therapeutic interventions that target the mitochondrial Achilles' heel, rendering cancer cells metabolically unviable or subverting endogenous MOMP inhibitors. A variety of experimental therapeutic agents can directly target mitochondria, causing apoptosis induction. This applies to a heterogeneous collection of chemically unrelated compounds including positively charged a-helical peptides, agents designed to mimic the Bcl-2 homology domain 3 of Bcl-2-like proteins, ampholytic cations, metals and steroid-like compounds. Such MOMP inducers or facilitators can induce apoptosis by themselves (monotherapy) or facilitate apoptosis induction in combination therapies, bypassing chemoresistance against DNA-damaging agents. In addition, it is possible to design molecules that neutralize inhibitor of apoptosis proteins (IAPs) or heat shock protein 70 (HSP70). Such IAP or HSP70 inhibitors can mimic the action of mitochondrion-derived mediators (Smac/DIABLO, that is, second mitochondria-derived activator of caspases/direct inhibitor of apoptosis-binding protein with a low isoelectric point, in the case of IAPs; AIF, that is apoptosis-inducing factor, in the case of HSP70) and exert potent chemosensitizing effects.

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“…Accumulation of senescent cells has long been viewed as potential cause of ageing (Campisi, 2005), and it has been shown that abnormally high levels of apoptosis achieved by genetically altering mitochondrial function leads to the premature appearance of age-related phenotypes (Kujoth et al, 2005). As described below, recent evidence supports the hypothesis that effective cancer suppression ultimately degrades tissue renewal capacity.…”

Section: Tumour-suppressing Mechansims Degrade Tissue Renewal Capacitymentioning

confidence: 89%

Relationships between stem cell exhaustion, tumour suppression and ageing

Ruzankina

Brown

2007

Br J Cancer

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Ageing is a complex process characterised by a variety of disorders associated with general organismal decline and an inability to maintain tissue homoeostasis. As described in this review, recent studies indicate that ageing may be caused, in part, by the depletion of stem and progenitor cells that govern tissue renewal. The potential causes of stem and progenitor cell attrition are numerous; however, a commonly accepted theory is that these cells are lost as a result of naturally occurring DNA damage and the obligate checkpoint responses that follow. Failure to launch appropriate responses to DNA damage is strongly associated with cancer initiation and progression. Therefore, it is at this nexus, the response to DNA damage, that an important organismal fate may be determined: to degrade regenerative potential for the purpose of preventing cancer. According to this viewpoint, ageing may be the unfortunate mark of successful cancer suppression in stem cells and other cell types. In this review, we will describe how degeneration of tissue renewal capacity links ageing and cancer suppression.

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Mitochondrial DNA Mutations, Oxidative Stress, and Apoptosis in Mammalian Aging

Cited by 1,858 publications

References 22 publications

Ageing and hearing loss

Ageing and hearing loss

Mitochondria as therapeutic targets for cancer chemotherapy

Relationships between stem cell exhaustion, tumour suppression and ageing

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