Mitochondria, oxidative DNA damage, and aging

Anson, R. Michael; Bohr, Vilhelm A.

doi:10.1007/s11357-000-0020-y

Cited by 20 publications

(19 citation statements)

References 165 publications

(147 reference statements)

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“…Age-associated changes in mitochondrial function and mitochondrial content have been implicated in the aging process and have been proposed to be a driving factor for the onset of sarcopenia (Anson and Bohr 2000;Jang et al 2010). An important aspect of mitochondrial health and homeostasis is the mtDNA content and copy number.…”

Section: Discussionmentioning

confidence: 99%

Loss of the antioxidant enzyme CuZnSOD (Sod1) mimics an age-related increase in absolute mitochondrial DNA copy number in the skeletal muscle

Masser

Clark

Remmen

et al. 2016

AGE

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Mitochondria contain multiple copies of the circular mitochondrial genome (mtDNA) that encodes ribosomal RNAs and proteins locally translated for oxidative phosphorylation. Loss of mtDNA integrity, both altered copy number and increased mutations, is implicated in cellular dysfunction with aging. Published data on mtDNA copy number and aging is discordant which may be due to methodological limitations for quantifying mtDNA copy number. Existing quantitative PCR (qPCR) mtDNA copy number quantification methods provide only relative abundances and are problematic to normalize to different template input amounts and across tissues/sample types. As well, existing methods cannot quantify mtDNA copy number in subcellular isolates, such as isolated mitochondria and neuronal synaptic terminals, which lack nuclear genomic DNA for normalization. We have developed and validated a novel absolute mtDNA copy number quantitation method that uses chip-based digital polymerase chain reaction (dPCR) to count the number of copies of mtDNA and used this novel method to assess the literature discrepancy in which there is no clear consensus whether mtDNA numbers change with aging in skeletal muscle. Skeletal muscle in old mice was found to have increased absolute mtDNA numbers compared to young controls. Furthermore, young Sod1 mice were assessed and show an age-mimicking increase in skeletal muscle mtDNA. These findings reproduce a number of previous studies that demonstrate age-related increases in mtDNA. This simple and cost effective dPCR approach should enable precise and accurate mtDNA copy number quantitation in mitochondrial studies, eliminating contradictory studies of mitochondrial DNA content with aging.

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Section: Discussionmentioning

confidence: 99%

Loss of the antioxidant enzyme CuZnSOD (Sod1) mimics an age-related increase in absolute mitochondrial DNA copy number in the skeletal muscle

Masser

Clark

Remmen

et al. 2016

AGE

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“…Although both oxidized bases block DNA polymerase, 8-oxodG is more mutagenic and is responsible for the characteristic G→T substitutions [135]. Other oxidative lesions include 8-hydroxyguanine, FAPy-adenine, 8-hydroxyadenine, 5,6-dihydroxyuracil, 5-hdroxyuracil, 5-hydroxycytosine, and 5-hydroxymethyluracil [5,8]. …”

Section: Disparities At the Nuclear Genome Level And Their Role Inmentioning

confidence: 99%

Mitochondrial determinants of cancer health disparities

Choudhury

Singh

2017

Seminars in Cancer Biology

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Mitochondria are involved in the generation of energy, cell growth and differentiation, cellular signaling, cell cycle control, and cell death. To date, the mitochondrial basis of cancer disparities is unknown. The goal of this review is to provide an understanding and a framework of mitochondrial determinants that may contribute to cancer disparities in racially different populations. Mitochondria, which are multi-functional, have been implicated in the initiation and progression of cancers in relation to metabolic alterations in transformed cells. Due to ethnic-based diversity, the mitochondrial genome (mtDNA) could be a basis for inherited racial disparities and for acquired somatic mutations during tumorigenesis. In African Americans, several germline, population-specific haplotype variants in mtDNA as well as depletion of mtDNA have been linked to cancer predisposition and cancer disparities. Indeed, depletion of mtDNA and mutations in mtDNA or nuclear genome (nDNA)-encoded mitochondrial proteins lead to mitochondrial dysfunction and promote resistance to apoptosis, the epithelial-to-mesenchymal transition, and metastatic disease, which in turn can contribute to cancer disparity and tumor aggressiveness related to racial disparities. Ethnic differences at the level of expression or genetic variations in nDNA encoding the mitochondrial proteome, including mitochondria-localized mtDNA replication and repair proteins, miRNA, transcription factors, kinases and phosphatases, and tumor suppressors and oncogenes may underlie susceptibility to high-risk and aggressive cancers found in African Americans and other ethnicities. The mitochondrial retrograde signaling that alters the expression profile of nuclear genes in response to dysfunctional mitochondria is a mechanism for tumorigenesis. In ethnic populations, differences in mitochondrial function may alter the cross talk between mitochondria and the nucleus at epigenetic and genetic levels, which can also contribute to cancer health disparities. Targeting mitochondrial determinants and mitochondrial retrograde signaling could provide a promising strategy for the development of selective anticancer therapy for dealing with cancer disparities. Further, agents that restore mitochondrial function to optimal levels should permit sensitivity to anticancer agents for the treatment of aggressive tumors that occur in racially diverse populations and hence help in reducing racial disparities.

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“…In fact, studies in long-lived species showed the presence of reduced oxidative damage [59], reduced mitochondrial free radical production [60], increased antioxidant defences [60] and increased resistance to oxidative stress both in vivo and in vitro [61]. However, a lack of correlation of oxidation with lifespan [62], or even an increase in oxidative damage/stress associated with long lifespan, has also been reported [63].…”

Section: Oxidative Stressmentioning

confidence: 99%

Genetic Factors Associated with Longevity in Humans

Beigrezaei¹,

Falcone²

2017

Senescence - Physiology or Pathology

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Introduction: Life expectancy and the rate of survival into old age have risen dramatically throughout the past century. The positive ageing outcomes may be due to a variety of factors including healthy lifestyle behaviors, but it is clear that longevity has a genetic basis, with heritability estimate of 20-35%. In this contest, it was emerged that human longevity seems strongly influenced by gender defined as the combination between biological sexual characteristics and factors related to behavior, social role, lifestyle and life experiences. Body-research methods: Successful ageing seems to be related to gene involved in different pathways of regulation, such as immune-inflammatory responses and oxidative stress. The aims of the present review are to discuss recent findings and highlight the genetic basis of longevity. For these reasons we are aimed to describe the most important underpinning which is the gender differences in longevity between males and females. Conclusion-key results: It appears clear that longevity may represent a complex polygenic trait that is influenced by the interaction of multiple genetic variants, as was demonstrated by several genetic studies conducted in the last years. Furthermore, epigenetic and environmental factors actin on the longevity phenotype.

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Mitochondria, oxidative DNA damage, and aging

Cited by 20 publications

References 165 publications

Loss of the antioxidant enzyme CuZnSOD (Sod1) mimics an age-related increase in absolute mitochondrial DNA copy number in the skeletal muscle

Loss of the antioxidant enzyme CuZnSOD (Sod1) mimics an age-related increase in absolute mitochondrial DNA copy number in the skeletal muscle

Mitochondrial determinants of cancer health disparities

Genetic Factors Associated with Longevity in Humans

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