Abstract
Mutations in mitochondrial DNA (mtDNA) lead to heteroplasmy, i.e., the intracellular coexistence of wild-type and mutant mtDNA strands, which impact a wide spectrum of diseases but also physiological processes, including endurance exercise performance in athletes. However, the phenotypic consequences of limited levels of naturally arising heteroplasmy have not been experimentally studied to date. We hence generated a conplastic mouse strain carrying the mitochondrial genome of an AKR/J mouse strain (B6-mtAKR) in a C57BL/6 J nuclear genomic background, leading to >20% heteroplasmy in the origin of light-strand DNA replication (OriL). These conplastic mice demonstrate a shorter lifespan as well as dysregulation of multiple metabolic pathways, culminating in impaired glucose metabolism, compared to that of wild-type C57BL/6 J mice carrying lower levels of heteroplasmy. Our results indicate that physiologically relevant differences in mtDNA heteroplasmy levels at a single, functionally important site impair the metabolic health and lifespan in mice.
Highlights
Mitochondria play a critical role in maintaining cellular activities by generating energy in the form of adenosine triphosphate (ATP)[1]
Deleterious mutations result in severe mitochondrial dysfunction and are causal for maternally inherited mitochondrial disease such as Leber’s hereditary optic neuropathy (LHON)[8] and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)[9]
We studied the impact of natural low-level heteroplasmy on aging, and demonstrated its consequences, including an impact on mitochondrial DNA (mtDNA) copy number ratio and the regulation of metabolic processes, which may be causative for a shorter lifespan
Summary
Mitochondria play a critical role in maintaining cellular activities by generating energy in the form of adenosine triphosphate (ATP)[1]. Since mitochondria are involved in such critical cellular activities, mitochondrial dysfunction has been linked to various degenerative and metabolic conditions (e.g., Alzheimer’s disease and diabetes), cancer, and aging in humans, as has been supported by experimental evidence[3,4,5,6]. The levels of the heteroplasmy varied between the C57BL/6 J and C57BL/6J-mtAKR/J strains Using this unique resource, we studied the impact of natural low-level heteroplasmy on aging, and demonstrated its consequences, including an impact on mtDNA copy number ratio and the regulation of metabolic processes, which may be causative for a shorter lifespan
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