Mitochondrial and nuclear DNA matching shapes metabolism and healthy ageing

Abstract

Human mitochondrial DNA (mtDNA) shows extensive within population sequence variability. Many studies suggest that mtDNA variants may be associated with ageing or diseases, although mechanistic evidence at the molecular level is lacking. Mitochondrial replacement has the potential to prevent transmission of disease-causing oocyte mtDNA. However, extension of this technology requires a comprehensive understanding of the physiological relevance of mtDNA sequence variability and its match with the nuclear-encoded mitochondrial genes. Studies in conplastic animals allow comparison of individuals with the same nuclear genome but different mtDNA variants, and have provided both supporting and refuting evidence that mtDNA variation influences organismal physiology. However, most of these studies did not confirm the conplastic status, focused on younger animals, and did not investigate the full range of physiological and phenotypic variability likely to be influenced by mitochondria. Here we systematically characterized conplastic mice throughout their lifespan using transcriptomic, proteomic,metabolomic, biochemical, physiological and phenotyping studies. We show that mtDNA haplotype profoundly influences mitochondrial proteostasis and reactive oxygen species generation,insulin signalling, obesity, and ageing parameters including telomere shortening and mitochondrial dysfunction, resulting in profound differences in health longevity between conplastic strains.

Assisted reproductive technologies to prevent human mitochondrial disease transmission

“…The divergence between human Eurasian and African mtDNAs has been mimicked in a mouse model (generated by backcrossing) in which a conplastic strain, B6-NZB, has a C57BL/6 (B6) nuclear genome and NZB/OlaHsd (NZB) cytoplasm 29 . B6-NZB mice unexpectedly exhibited a median lifespan extended by 16%, manifesting no decline in respiration and fewer signs of aging compared with B6 controls.…”

“…B6-NZB mice unexpectedly exhibited a median lifespan extended by 16%, manifesting no decline in respiration and fewer signs of aging compared with B6 controls. The study reports that mtDNA haplotype influences mitochondrial proteostasis, metabolic syndrome and reactive oxygen species generation 29 . Mouse models suggest that metabolic syndrome is transmitted via mitochondria transgenerationally owing to defective mitophagy (destruction of mitochondria by the cell) 30,31 .…”

Prévenir la transmission des mutations de l’ADN mitochondrial par don de cytoplasme : où en est-on ?

“…The recent birth from a mitochondrial DNA mutation carrier of a child, conceived after transfer in a donor oocyte nucléaire, sont capables de modifier les apprentissages, les capacités exploratrices, le développement sensoriel, et l'anatomie cérébrale de ces animaux [12]. Une étude très récente a montré par ailleurs que l'échange des ADNmt entre 2 lignées de souris peut s'accompagner d'une amélioration de leur état de santé au fil du temps (en particulier, diminution des cas d'obésité, de diabète, et médiane de durée de vie allongée) [13]. Ces études montrent que des ADNmt différents, en interaction avec un même génome nucléaire, sont capables de modifier des fonctions cognitives essentielles.…”

The CNIC

“…Among many landmark studies, some recent representative stories include discoveries of the biology of neutrophil and platelet recruitment during acute injury, 1 mitochondrial DNA (mtDNA) in ageing, 2 and the implication of mutations in genes of the NOTCH signaling pathway in inherited cardiomyopathies. 3 CNIC researchers recently found that vascular damage during acute injury in different organs is caused by the concerted action between neutrophils and platelets, and only when productive interactions with activated platelets occur do neutrophils undergo secondary activation, and pathological inflammation ensues causing irreversible tissue damage.…”