Dataset Information

Maternally Inherited Differences within Mitochondrial Complex I Control Murine Healthspan.

ABSTRACT: Mitochondrial complex I-the largest enzyme complex of the mitochondrial oxidative phosphorylation machinery-has been proposed to contribute to a variety of age-related pathological alterations as well as longevity. The enzyme complex-consisting proteins are encoded by both nuclear (nDNA) and mitochondrial DNA (mtDNA). While some association studies of mtDNA encoded complex I genes and lifespan in humans have been reported, experimental evidence and the functional consequence of such variants is limited to studies using invertebrate models. Here, we present experimental evidence that a homoplasmic mutation in the mitochondrially encoded complex I gene mt-Nd2 modulates lifespan by altering cellular tryptophan levels and, consequently, ageing-related pathways in mice. A conplastic mouse strain carrying a mutation at m.4738C > A in mt-Nd2 lived slightly, but significantly, shorter than the controls did. The same mutation led to a higher susceptibility to glucose intolerance induced by high-fat diet feeding. These phenotypes were not observed in mice carrying a mutation in another mtDNA encoded complex I gene, mt-Nd5, suggesting the functional relevance of particular mutations in complex I to ageing and age-related diseases.

SUBMITTER: Hirose M

PROVIDER: S-EPMC6678443 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Maternally Inherited Differences within Mitochondrial Complex I Control Murine Healthspan.

Hirose Misa M Schilf Paul P Zarse Kim K Busch Hauke H Fuellen Georg G Jöhren Olaf O Köhling Rüdiger R König Inke R IR Richer Barbara B Rupp Jan J Schwaninger Markus M Seeger Karsten K Sina Christian C Ristow Michael M Ibrahim Saleh M SM

Genes 20190713 7

Mitochondrial complex I-the largest enzyme complex of the mitochondrial oxidative phosphorylation machinery-has been proposed to contribute to a variety of age-related pathological alterations as well as longevity. The enzyme complex-consisting proteins are encoded by both nuclear (nDNA) and mitochondrial DNA (mtDNA). While some association studies of mtDNA encoded complex I genes and lifespan in humans have been reported, experimental evidence and the functional consequence of such variants is ...[more]

PMID: 31337008

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Project description:BackgroundNuclear genes or family-based mitochondrial screening have been the focus of genetic studies into essential hypertension. Studies into the role of mitochondria in sporadic Chinese hypertensives are lacking. The objective of the study was to explore the relationship between mitochondrial DNA (mtDNA) variations and the development of maternally inherited essential hypertension (MIEH) in China.MethodsYangzhou residents who were outpatients or in-patients at the Department of Cardiology in Northern Jiangsu People's Hospital (Jiangsu, China) from June 2009 to June 2015 were recruited in a 1:1 case control study of 600 gender-matched Chinese MIEH subjects and controls. Genomic DNA was isolated from whole blood cells. The most likely sites for hypertension were screened using oligodeoxynucleotides at positions 7908-8816, purified and subsequently analyzed by direct sequencing according to the revised consensus Cambridge sequence. The frequency, density, type and conservative evolution of mtDNA variations were comprehensively analyzed.ResultsWe found a statistical difference between the two groups for body mass index, waist circumference, abdominal circumference, triglyceride, low-density lipoprotein cholesterol, fasting blood glucose, uric acid, creatinine and blood urea nitrogen (P < 0.05). More amino-acid changes and RNA variants were found in MIEH subjects than the controls (P < 0.01). The detection system simultaneously identified 40 different heteroplasmic or homoplasmic mutations in 4 genes: COXII, tRNALys, ATP8 and ATP 6. The mtDNA variations were mainly distributed in regions of ATP6 binding sites, and the site of highest mutation frequency was m. 8414C > T. Three changes in single bases (C8414T in ATP8, A8701G in ATP6 and G8584A in ATP6) were significantly different in the MIEH patients and the controls (P < 0.001). The m.8273_8281del mutation was identified from 59 MIEH patients.ConclusionsOur results indicate that novel mtDNA mutations may be involved in the pathological process of MIEH, and mitochondrial genetic characteristics were identified in MIEH individuals.

Dataset Information

Maternally Inherited Differences within Mitochondrial Complex I Control Murine Healthspan.

Publications

Maternally Inherited Differences within Mitochondrial Complex I Control Murine Healthspan.

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