Oxidative stress is not an obligate mediator of disease provoked by mitochondrial DNA mutations

Mott, Justin L.; Zhang, Dekui; Stevens, Melissa; Chang, Shin Wen; Denniger, Grace; Zassenhaus, Hans Peter

doi:10.1016/s0027-5107(00)00159-7

Cited by 47 publications

(32 citation statements)

References 42 publications

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“…More recently, the accumulation of deletions in mtDNA has been shown to correlate with increasing age (7), and a current longitudinal study strongly supports the age-dependent accumulation of non-inherited point mutations in human mtDNA (8). Recent data suggest that mutations in mtDNA can suppress apoptosis, a situation that would favor the growth of tumor cells (9). Additionally, human somatic cancer cells can acquire a homoplasmic mutant mtDNA genotype, presumably by mitotic segregation of mutant mitochondria during proliferation of tumors (10).…”

supporting

confidence: 72%

The Fidelity of Human DNA Polymerase γ with and without Exonucleolytic Proofreading and the p55 Accessory Subunit

Longley¹,

Nguyen²,

Kunkel³

et al. 2001

Journal of Biological Chemistry

231

195

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Mutations in human mitochondrial DNA influence aging, induce severe neuromuscular pathologies, cause maternally inherited metabolic diseases, and suppress apoptosis. Since the genetic stability of mitochondrial DNA depends on the accuracy of DNA polymerase ␥ (pol ␥), we investigated the fidelity of DNA synthesis by human pol ␥. Comparison of the wild-type 140-kDa catalytic subunit to its exonuclease-deficient derivative indicates pol ␥ has high base substitution fidelity that results from high nucleotide selectivity and exonucleolytic proofreading. pol ␥ is also relatively accurate for single-base additions and deletions in non-iterated and short repetitive sequences. However, when copying homopolymeric sequences longer than four nucleotides, pol ␥ has low frameshift fidelity and also generates base substitutions inferred to result from a primer dislocation mechanism. The ability of pol ␥ both to make and to proofread dislocation intermediates is the first such evidence for a family A polymerase. Including the p55 accessory subunit, which confers processivity to the pol ␥ catalytic subunit, decreases frameshift and base substitution fidelity. Kinetic analyses indicate that p55 promotes extension of mismatched termini to lower the fidelity. These data suggest that homopolymeric runs in mitochondrial DNA may be particularly prone to frameshift mutation in vivo due to replication errors by pol ␥.

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supporting

confidence: 72%

The Fidelity of Human DNA Polymerase γ with and without Exonucleolytic Proofreading and the p55 Accessory Subunit

Longley¹,

Nguyen²,

Kunkel³

et al. 2001

Journal of Biological Chemistry

231

195

View full text Add to dashboard Cite

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“…In fact, direct measurement of free radical leak at complexes I and III in D257A mice also shows that ROS production is not elevated at these sites in the mitochondria. 3 These observations are supported by similar recent data (12) and are also consistent with a lack of oxidative damage in a transgenic mouse model with heart-specific elevation of mtDNA mutations (13). Of course, the absence of increased steady-state levels of oxidative stress functioning downstream of a high mitochondrial mutational load does not preclude a role for oxidative damage in the generation of mtDNA mutations during natural aging.…”

Section: Oxidative Stress or Cell Death?supporting

confidence: 74%

Mitochondrial DNA Mutations and Apoptosis in Mammalian Aging

2006

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Mutations in mitochondrial DNA (mtDNA) accumulate during aging, but their significance to longevity and age-associated disease has been uncertain. Recently, in support of the hypothesis that mtDNA integrity is important, we have shown that age-associated diseases arise more rapidly in mice where mtDNA mutations and increased levels of apoptosis occur at higher rates than normal due to expression of an error-prone mtDNA polymerase. Further studies in this model may provide deeper insights into the relationship between mitochondria, aging, and susceptibility to age-associated diseases, such as cancer. (Cancer Res 2006; 66(15): 7386-9) Mitochondrial DNA Mutations and Aging Mitochondria contain their own f16.5-kb circular DNA encoding essential subunits of the electron transport chain complexes as well as the tRNAs and rRNAs necessary for their translation. Because of the high gene density of the mitochondrial genome, mutations in mitochondrial DNA (mtDNA) have a high likelihood of affecting the expression or coding sequence of mitochondrial genes. This susceptibility to deleterious mutations is offset to an extent by the presence of multiple copies of the mitochondrial genome in every cell.Point mutations and deletions in mtDNA accumulate with age in a wide variety of tissues in multiple species (1-7), and there is evidence to suggest that there can be functional consequences with respect to mitochondrial bioenergetics. Loss of cytochrome c oxidase activity has been correlated with the presence of mtDNA deletions in serial sections of aged muscle fibers (8), and clonal expansion of cytochrome c oxidase-deficient cells bearing pathogenic mtDNA point mutations in aged intestinal crypts has been reported (9). Until recently, however, the association between mtDNA mutations and aging has remained correlative. We (10) and others (11) have now addressed this issue by generating mice that display elevated mtDNA mutation frequencies throughout their tissues [3-11 times higher than wild-type (WT) mice] due to errorprone replication by an exonuclease-deficient derivative of the nuclear-encoded mtDNA polymerase g. These mitochondrial mutator (Polg D257A , herein called D257A) mice display a large array of phenotypes resembling aspects of accelerated aging; these include reduced life span, hair graying and alopecia, cardiac enlargement with functional alterations, muscle loss, reduced fertility, accelerated thymic involution, kyphosis, and decreased bone density, and age-related hearing loss (presbycusis). Additionally, these mice become anemic and display loss of intestinal crypts or disorganized villar structures. The accumulation of mtDNA mutations in D257A mice begins early in development (12), in contrast to observations in human tissues, where substantially increased frequencies of mtDNA mutations do not occur until after the 4th or 5th decade of life (2, 4, 7). In young adult WT mice, we have observed that levels of mtDNA mutations are quite high, averaging 3 to 10 mutations per mtDNA genome in tissues from 5...

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“…Another group reported that transgenic mice expressing heart-specific mutPOLG suffered from a cardiomyopathy attributable to an accumulation of mtDNA defects (Zhang et al, 2000). Nevertheless, neither an abnormality of mitochondrial respiration nor a loss of ATP could be detected in the hearts of these mice (Mott et al, 2001;Zhang et al, 2003). More studies are still needed to elucidate the mechanisms by which mtDNA defects alter mitochondrial Ca 2ϩ uptake.…”

Section: Possible Role Of Mitochondrial Camentioning

confidence: 99%

Abnormal Ca²⁺Dynamics in Transgenic Mice with Neuron-Specific Mitochondrial DNA Defects

Kubota¹,

Kasahara²,

Nakamura³

et al. 2006

J. Neurosci.

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Maintenance of mitochondrial DNA (mtDNA) depends on nuclear-encoded proteins such as mtDNA polymerase (POLG), whose mutations are involved in the diseases caused by mtDNA defects including mutation and deletion. The defects in mtDNA and in intracellular Ca 2ϩ ([Ca 2ϩ ] i ) homeostasis have been reported in bipolar disorder (BD). To understand the relevance of the mtDNA defects to BD, we studied transgenic (Tg) mice in which mutant POLG (mutPOLG) was expressed specifically in neurons. mtDNA defects were accumulated in the brains of mutPOLG Tg mice in an age-dependent manner and the mutant mice showed BD-like behavior. However, the molecular and cellular basis for the abnormalities has not been clarified. ] i dynamics, which may be involved in the pathogenesis of BD.

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Oxidative stress is not an obligate mediator of disease provoked by mitochondrial DNA mutations

Cited by 47 publications

References 42 publications

The Fidelity of Human DNA Polymerase γ with and without Exonucleolytic Proofreading and the p55 Accessory Subunit

The Fidelity of Human DNA Polymerase γ with and without Exonucleolytic Proofreading and the p55 Accessory Subunit

Mitochondrial DNA Mutations and Apoptosis in Mammalian Aging

Abnormal Ca²⁺Dynamics in Transgenic Mice with Neuron-Specific Mitochondrial DNA Defects

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Oxidative stress is not an obligate mediator of disease provoked by mitochondrial DNA mutations

Cited by 47 publications

References 42 publications

The Fidelity of Human DNA Polymerase γ with and without Exonucleolytic Proofreading and the p55 Accessory Subunit

The Fidelity of Human DNA Polymerase γ with and without Exonucleolytic Proofreading and the p55 Accessory Subunit

Mitochondrial DNA Mutations and Apoptosis in Mammalian Aging

Abnormal Ca2+Dynamics in Transgenic Mice with Neuron-Specific Mitochondrial DNA Defects

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Abnormal Ca²⁺Dynamics in Transgenic Mice with Neuron-Specific Mitochondrial DNA Defects