Mitochondrial OxPhos: the integrator of the cellular metabolic status

Abstract

The oxidative phosphorylation (OXPHOS) system is the only process in animal cells with components encoded by two genomes, mitochondrial DNA (mtDNA) and nuclear DNA (nDNA). MtDNA is polyploid, maternally inherited, suffers marginal recombination and has a rate of mutation which is one order of magnitude higher than nDNA, thus resulting in high variability of healthy mtDNA haplotypes. Nuclear OXPHOS genes present lower mutation rate and recombination. However they have alternative options due to allele variants and tissue-specific variants, which confront identical nDNA with diverse mtDNA within the same individual. This asymmetry leads to the physical match constraint: the fact that mtDNA-encoded proteins have to physically assemble with the nuclearencoded ones to build the respiratory complexes. All mtDNAs of a given cell are essentially identical, a situation termed homoplasmy. Heteroplasmy refers to the presence of more than one variant of mtDNA co-existing in the same cytoplasm. Two major interconnected questions remain to be solved: (i) are different versions of wild-type mtDNAs interchangeable without any phenotypic impact? And, (ii) does the iatrogenic introduction of heteroplasmy result in health risks for the offspring by triggering a genomic conflict between alternative mtDNA variants with potential negative consequences? We intend to understand the long-term consequences of mtDNA/nDNA mismatch and heteroplasmy. In particular, (i) whether or not modifications in key nuclear genes involved in mitochondrial function modulate the impact of alternative mtDNAs, (ii) whether or not the co-existence of two wild-type mtDNAs in the same cytoplasm impacts on metabolism, and (iii) the identification of the signals involved in regulation. To address these questions, we use conplastic mice (identical nucleus but interchanged mtDNAs, C57 and NZB non-pathological variants) and heteroplasmic mice (co-existence of both mtDNAs in the same cell). Here, we systematically characterised conplastic mice throughout embryo development and during their lifespan through omics techniques and physiological and phenotyping studies. We report that the mtDNA haplotype profoundly influences the reactive oxygen species generation, energy homeostasis, metabolism and ageing parameters among others, resulting in different healthy longevities of conplastic strains. Our recent analysis supports: (1) mtDNA variants induce functional OXPHOS differences under the same nuclear background. (2) Cells can adapt their OXPHOS performance to generate healthy animals, regardless the nDNA/mtDNA match. (3) Different cell types show specific sensitivity to the nDNA/mtDNA match. (4) Changes in the nDNA/mtDNA match induce significant metabolic differences that are manifested in the adulthood and which dramatically impact on ageing and longevity. Heteroplasmy is actively combated by several mechanisms, including the degradation of the paternal mtDNA upon fertilization, and the existence of a genetic mtDNA bottleneck in oocyte development. Heteroplasmy can be naturally generated by mutagenesis during mtDNA replication, but also can originate from novel medical technologies aiming (i) to prevent the transmission of mtDNA-linked diseases, (ii) to improve the fertility by human oocyte “rejuvenation”, and (iii) to restore the function of damaged cells using the transfer of foreign mitochondria. Here we show that mtDNA heteroplasmy modulates the viability and metabolism of embryonic cells, as well as their ability to become iPS. During post-natal life, most of the tissues can remove the remaining heteroplasmy and preserve life-long fitness. In contrast, critical tissues like cardiac and skeletal muscles as well as the lung maintain heteroplasmy and suffer a progressive metabolic stress leading to a severe adult pathologies, including cardiopulmonary failure, skeletal muscle wasting, frailty and premature death.