Accumulation of point mutations in mitochondrial DNA of aging mice

Khaidakov, Magomed; Heflich, Robert H.; Manjanatha, Mugimane G.; Myers, Meagan B.; Aidoo, Anane

doi:10.1016/s0027-5107(03)00010-1

Cited by 107 publications

(77 citation statements)

References 47 publications

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“…Approximately 65% of the point mutations in all groups were A:T to G:C transitions (data not shown). A similar distribution of point mutations in association with aging has been reported previously (19,32).…”

Section: Figuresupporting

confidence: 86%

“…Scale bars: 100 μm. of the additional point mutations are transitions, as also reported by others in aging mice (19,32), whereas 8-OHdG leads mainly to transversions (48). We conclude that, although the increased level of 8-OHdG is a well-known indicator of oxidative stress, the point mutations we observe are unlikely to be a direct consequence of this modified base.…”

Section: Figuresupporting

confidence: 86%

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Senescence-associated phenotypes in Akita diabetic mice are enhanced by absence of bradykinin B2 receptors

Kakoki¹

2006

Journal of Clinical Investigation

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We have previously reported that genetically increased angiotensin-converting enzyme levels, or absence of the bradykinin B2 receptor, increase kidney damage in diabetic mice. We demonstrate here that this is part of a more general phenomenon -diabetes and, to a lesser degree, absence of the B2 receptor, independently but also largely additively when combined, enhance senescence-associated phenotypes in multiple tissues. Thus, at 12 months of age, indicators of senescence (alopecia, skin atrophy, kyphosis, osteoporosis, testicular atrophy, lipofuscin accumulation in renal proximal tubule and testicular Leydig cells, and apoptosis in the testis and intestine) are virtually absent in WT mice, detectable in B2 receptor-null mice, clearly apparent in mice diabetic because of a dominant mutation (Akita) in the Ins2 gene, and most obvious in Akita diabetic plus B2 receptor-null mice. Renal expression of several genes that encode proteins associated with senescence and/or apoptosis (TGF-β1, connective tissue growth factor, p53, α-synuclein, and forkhead box O1) increases in the same progression. Concomitant increases occur in 8-hydroxy-2′-deoxyguanosine, point mutations and deletions in kidney mitochondrial DNA, and thiobarbituric acid-reactive substances in plasma, together with decreases in the reduced form of glutathione in erythrocytes. Thus, absence of the bradykinin B2 receptor increases the oxidative stress, mitochondrial DNA damage, and many senescence-associated phenotypes already present in untreated Akita diabetic mice.

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Section: Figuresupporting

confidence: 86%

Section: Figuresupporting

confidence: 86%

Senescence-associated phenotypes in Akita diabetic mice are enhanced by absence of bradykinin B2 receptors

Kakoki¹

2006

Journal of Clinical Investigation

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“…Mutations and deletions of mtDNA were observed during aging (16,17). Increased mutations and deletions of mtDNA in mice with defective mitochondrial DNA polymerase are associated with reduced life span (18).…”

Section: Rosmentioning

confidence: 99%

Replicative Senescence Induced by Romo1-derived Reactive Oxygen Species

Chung

Lee

Kim

et al. 2008

Journal of Biological Chemistry

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Persistent accumulation of DNA damage induced by reactive oxygen species (ROS) is proposed to be a major contributor toward the aging process. Furthermore, an increase in age-associated ROS is strongly correlated with aging in various species, including humans. Here we showed that the enforced expression of the ROS modulator 1 (Romo1) triggered premature senescence by ROS production, and this also contributed toward induction of DNA damage. Romo1-derived ROS was found to originate in the mitochondrial electron transport chain. Romo1 expression gradually increased in proportion to population doublings of IMR-90 human fibroblasts. An increase in ROS production in these cells with high population doubling was blocked by the Romo1 knockdown using Romo1 small interfering RNA. Romo1 knockdown also inhibited the progression of replicative senescence. Based on these results, we suggest that age-related ROS levels increase, and this contributes to replicative senescence, which is directly associated with Romo1 expression.The chromosomal ends of senescent cells are associated with DNA damage-response factors. Telomere shortening triggers a DNA damage checkpoint response, resulting in replicative senescence. Blocking of the DNA damage checkpoint response releases cell cycle arrest in the G 1 phase of the cell (1). One of the important mediators in telomere-dependent senescence is p53, and it plays an important role in DNA damage response as well as regulation of cellular senescence. The other main regulators of senescence are reported as p21 WAF1/CIP1 , p16 INK4A , and retinoblastoma protein, and these have been classified into two major signaling pathways, the p53/p21 WAF1/CIP1 pathway and the p16

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“…Persistence of this damage would be expected to cause a high mutation rate in mtDNA. Thus, it is not surprising that mutations, including deletions, duplications, and point mutations, have been found to accumulate in mtDNA in a variety of tissues during aging in humans, monkeys, and rodents (68)(69)(70)(71)(72)(73) and cause a mosaic pattern of respiratory chain deficiency in pre-and post-mitotic tissues. The most frequent and best characterized age-associated mtDNA mutation is a 4977-bp deletion also called the "common deletion".…”

Section: Mitochondrial Dna Repair and Agingmentioning

confidence: 99%