Mitochondrial point mutations do not limit the natural lifespan of mice

Vermulst, Marc; Bielas, Jason H.; Kujoth, Gregory C.; Ladiges, Warren; Rabinovitch, Peter S.; Prolla, Tomas A.; Loeb, Lawrence A.

doi:10.1038/ng1988

Cited by 355 publications

(396 citation statements)

References 27 publications

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“…The mutations detected were mainly transitions, characteristic of mutation following oxidative stress (30). Interestingly, the mutation spectrum was independent of the in vivo hypoxia level.…”

Section: Discussionmentioning

confidence: 92%

Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis

Biniecka¹,

Fox²,

Gao³

et al. 2011

Arthritis & Rheumatism

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Objective. To assess the levels and spectrum of mitochondrial DNA (mtDNA) point mutations in synovial tissue from patients with inflammatory arthritis in relation to in vivo hypoxia and oxidative stress levels.Methods. Random Mutation Capture assay was used to quantitatively evaluate alterations of the synovial mitochondrial genome. In vivo tissue oxygen levels (tPO 2 ) were measured at arthroscopy using a Results. The median tPO 2 level in synovial tissue indicated significant hypoxia (25.47 mm Hg). Higher frequency of mtDNA mutations was associated with reduced in vivo oxygen tension (P ‫؍‬ 0.05) and with higher synovial 4-HNE cytoplasmic expression (P ‫؍‬ 0.04). Synovial expression of CytcO II correlated with in vivo tPO 2 levels (P ‫؍‬ 0.03), and levels were lower in patients with tPO 2 <20 mm Hg (P < 0.05). In vitro levels of mtDNA mutations, ROS, mitochondrial membrane potential, 8-oxo-dG, and 4-HNE were higher in synoviocytes exposed to 1% hypoxia (P < 0.05); all of these increased levels were rescued by SOD and DMOG and, with the exception of ROS, by NAC.Conclusion. These findings demonstrate that hypoxia-induced mitochondrial dysfunction drives mitochondrial genome mutagenesis, and antioxidants significantly rescue these events.

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Section: Discussionmentioning

confidence: 92%

Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis

Biniecka¹,

Fox²,

Gao³

et al. 2011

Arthritis & Rheumatism

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“…Corroborating the notion that mtDNA deletions may contribute to neurodegeneration in PD, increased levels of mtDNA deletions have been observed in the striatum and in substantia nigra (SN) neurons of PD patients; however, the role of single base pair mutations, polymorphisms and haplogroups in human PD remains controversial (118). Importantly, previous methods of measuring mtDNA mutations have recently been called into question, supporting a more conservative interpretation of the data associating accumulation of mtDNA mutations and age (113). Overall, studies of mtDNA deletions and mutations in the context of PD suggest that the mitochondrial genome may be involved in the pathogenesis of PD, but additional genetic and functional studies are necessary to further elucidate this proposed connection.…”

Section: Fig 1 Dysregulated Mitochondrial Dynamics In Parkin-mentioning

confidence: 99%

Toxin Models of Mitochondrial Dysfunction in Parkinson's Disease

Martinez

Greenamyre

2012

Antioxidants & Redox Signaling

228

155

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Significance: Parkinson's disease (PD) is a neurodegenerative disorder characterized, in part, by the progressive and selective loss of dopaminergic neuron cell bodies within the substantia nigra pars compacta (SNpc) and the associated deficiency of the neurotransmitter dopamine (DA) in the striatum, which gives rise to the typical motor symptoms of PD. The mechanisms that contribute to the induction and progressive cell death of dopaminergic neurons in PD are multi-faceted and remain incompletely understood. Data from epidemiological studies in humans and molecular studies in genetic, as well as toxin-induced animal models of parkinsonism, indicate that mitochondrial dysfunction occurs early in the pathogenesis of both familial and idiopathic PD. In this review, we provide an overview of toxin models of mitochondrial dysfunction in experimental Parkinson's disease and discuss mitochondrial mechanisms of neurotoxicity. Recent Advances: A new toxin model using the mitochondrial toxin trichloroethylene was recently described and novel methods, such as intranasal exposure to toxins, have been explored. Additionally, recent research conducted in toxin models of parkinsonism provides an emerging emphasis on extranigral aspects of PD pathology. Critical Issues: Unfortunately, none of the existing animal models of experimental PD completely mimics the etiology, progression, and pathology of human PD. Future Directions: Continued efforts to optimize established animal models of parkinsonism, as well as the development and characterization of new animal models are essential, as there still remains a disconnect in terms of translating mechanistic observations in animal models of experimental PD into bona fide diseasemodifying therapeutics for human PD patients. Antioxid. Redox Signal. 16, 920-934.

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“…Mutation frequency in mtDNA was quantified by the random mutation capture assay, as described previously (24). This methodology is a single-molecule sequencing approach, which selects mutation sites by digesting wild-type molecules at a known restriction site (TaqI).…”

Section: Methodsmentioning

confidence: 99%

Aging Neural Progenitor Cells Have Decreased Mitochondrial Content and Lower Oxidative Metabolism

Stoll

Cheung

Mikheev

et al. 2011

Journal of Biological Chemistry

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Background: Mitochondrial dysfunction occurs in many tissues during normal aging. Results: Aged neural progenitor cells (NPCs) have decreased regenerative capacity, fewer functional mitochondria, and less oxygen consumption compared with young adult NPCs. Conclusion: Coordinated changes in proteomics, subcellular structure, and physiology demonstrate an altered metabolic strategy in aged NPCs. Significance: Such alterations may explain the age-dependent responses to hypoxia encountered during tumor or stroke.

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Mitochondrial point mutations do not limit the natural lifespan of mice

Cited by 355 publications

References 27 publications

Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis

Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis

Toxin Models of Mitochondrial Dysfunction in Parkinson's Disease

Aging Neural Progenitor Cells Have Decreased Mitochondrial Content and Lower Oxidative Metabolism

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