The Role of Mitochondrial DNA Mutations in Mammalian Aging

Kujoth, Gregory C.; Bradshaw, Patrick C.; Haroon, Suraiya; Prolla, Tomas A.

doi:10.1371/journal.pgen.0030024

Cited by 166 publications

(116 citation statements)

References 167 publications

(192 reference statements)

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“…rate-a vicious circle eventually causing ageing (figure 1). This model has been supported by various observations, including the inverse relationship between mitochondrial oxidative damage marker concentration and maximum lifespan in mammals (Barja & Herrero 2000), and the report of increased mtDNA mutation load in aged cells (Kujoth et al 2007).…”

Section: Mitochondrial Mutation and Ageingsupporting

confidence: 54%

Mitochondrial whims: metabolic rate, longevity and the rate of molecular evolution

et al. 2009

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The evolutionary rate of mitochondrial DNA (mtDNA) is highly variable across lineages in animals, and particularly in mammals. This variation has been interpreted as reflecting variations in metabolic rate: mitochondrial respiratory activity would tend to generate mutagenic agents, thus increasing the mutation rate. Here we review recent evidence suggesting that a direct, mechanical effect of species metabolic rate on mtDNA evolutionary rate is unlikely. We suggest that natural selection could act to reduce the (somatic) mtDNA mutation rate in long-lived species, in agreement with the mitochondrial theory of ageing.

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Section: Mitochondrial Mutation and Ageingsupporting

confidence: 54%

Mitochondrial whims: metabolic rate, longevity and the rate of molecular evolution

et al. 2009

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“…Therefore it seems conceivable that any enhancement of oxidative stress by external or internal conditions will initiate the apoptotic cascade in deletion bearing cells. An ongoing apoptosis may exhaust stem cell renewal capacities, leading to the ageing phenotype with features such as hair greying, cardiac enlargement or sarcopenia (Kujoth et al, 2005;Kujoth et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, mitochondria play a key role in the initiation of the apoptotic cascade, which may also play a role in the pathology of the ageing phenotype (Kujoth et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

The 4977bp deletion of mitochondrial DNA in human skeletal muscle, heart and different areas of the brain: A useful biomarker or more?

Meißner

Bruse

Mohamed

et al. 2008

Experimental Gerontology

140

117

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It has been suggested that deletions of mitochondrial DNA (mtDNA) are important players with regard to the ageing process. Since the early 1990s, the 4977 bp deletion has been studied in various tissues, especially in postmitotic tissues with high energy demand. Unfortunately, some of these studies included less than 10 subjects, so the aim of our study was to quantify reliable the deletion amount in nine different regions of human brain, heart and skeletal muscle in a cohort of 92 individuals. The basal ganglia contain the highest deletion amounts with values up to 2.93% and differences in deletion levels between early adolescence and older ages were up to three orders of magnitude. Values in frontal lobe were on average an order of magnitude lower, but lowest in cerebellar tissue where the amount was on average only 5 x 10 -3 of the basal ganglia. The deletion started to accumulate in iliopsoas muscle early in the fourth decade of life with values between 0.00019% and 0.0035% and was highest in a 102 year-old woman with 0.14%. In comparison to skeletal muscle, the overall abundance in heart muscle of the left ventricle was only one third. The best linear logarithmic correlation between amount of the deletion and age was found in substanta nigra with r=0.87 (p<0.0005) followed by anterior wall of the left ventricle (r=0.82; p<0.0005). With regard to mitochondrial DNA damage, we propose to use the 4977 bp deletion as an ideal biomarker to discriminate between physiological ageing and accelerated ageing. The biological meaning of mitochondrial deletions in the process of ageing is under discussion, but there is experimental evidence that large-scale deletions impair the oxidative phosphorylation in single cells and sensitize these cells to undergo apoptosis.

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“…Indeed, mtDNA with large deletions has been reported to accumulate with aging in various tissues of various mammalian species (reviewed by Kujoth et al [7]). Although these observations do not address whether the accumulation of mutated mtDNA has a causal role in aging, they suggest that mutated mtDNA serves as a useful biomarker of aging regardless of the lifespan of specific organisms.…”

Section: Mitochondrial Dna Mutations and Oxidative Stress In The Aginmentioning

confidence: 99%

“…The mammalian central nervous system (CNS) is not an exception. Several reports have presented clear age-dependent increases in the amount of deleted mtDNA in the brains of rodents and human [7]. Although in these reports the fraction of deleted mtDNA was estimated to be very low (less than 1%), recent studies that employed single-cell dissection in combination with quantitative real-time PCR showed that, in the human substantia nigra neurons of elderly subjects, deleted mutant mtDNA species accumulate to up to ~45% of total mtDNA [8,9].…”

Section: Mitochondrial Dna Mutations and Oxidative Stress In The Aginmentioning

confidence: 99%

The mitochondrial impairment, oxidative stress and neurodegeneration connection: reality or just an attractive hypothesis?

Fukui

Moraes

2008

Trends in Neurosciences

220

143

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Aging is the most important risk factor for common neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. Aging in the central nervous system has been associated with elevated mutation load in mitochondrial DNA, defects in mitochondrial respiration and increased oxidative damage. These observations support a 'vicious cycle' theory which states that there is a feedback mechanism connecting these events in aging and age-associated neurodegeneration. Despite being an extremely attractive hypothesis, the bulk of the evidence supporting the mitochondrial vicious cycle model comes from pharmacological experiments in which the modes of mitochondrial enzyme inhibition are far from those observed in real life. Furthermore, recent in vivo evidence does not support this model. In this review, we focus on the relationship among the components of the putative vicious cycle, with particular emphasis on the role of mitochondrial defects on oxidative stress. Mitochondrial respiratory chain and reactive oxygen species productionMitochondria, being the key players in ATP production and diverse cell signaling events, are essential organelles for the survival of eukaryotic cells. Unlike all other organelles in animals, the mitochondria have their own genome (mitochondrial DNA; mtDNA) that encodes components of the oxidative phosphorylation (OXPHOS) system. The mitochondrial OXPHOS machinery is composed of five multisubunit complexes (complex I-V). From Krebs cycle intermediates (NADH and FADH 2 ), electrons feed into complex I or II, and are transferred to complex III, then to complex IV, and finally to O 2 . The redox energy released during the electron transfer process in complexes I, III and IV is utilized to actively pump out H + from the mitochondrial matrix to the intermembrane space, generating the electrochemical gradient of H + across the inner membrane which is ultimately utilized by complex V to produce ATP [1].This elegant system for energy production, however, is not perfect. A small portion (up to 2%) of electrons passing through the electron transport chain, mostly at complex I and complex III, react with molecular oxygen and yield superoxide anion, which can be converted into other reactive oxygen species (ROS) such as hydrogen peroxide and the highly reactive hydroxyl radical through enzymatic and nonenzymatic reactions [2]. Cells are endowed with robust endogenous antioxidant systems to counteract excessive ROS. It is believed that ROS, in particular hydrogen peroxide, have physiological roles as signaling molecules [3,4]. However,

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The Role of Mitochondrial DNA Mutations in Mammalian Aging

Cited by 166 publications

References 167 publications

Mitochondrial whims: metabolic rate, longevity and the rate of molecular evolution

Mitochondrial whims: metabolic rate, longevity and the rate of molecular evolution

The 4977bp deletion of mitochondrial DNA in human skeletal muscle, heart and different areas of the brain: A useful biomarker or more?

The mitochondrial impairment, oxidative stress and neurodegeneration connection: reality or just an attractive hypothesis?

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