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Human mitochondrial DNA (mtDNA) shows extensive within-population sequence variability (1). Many studies suggest that mtDNA variants may be associated with ageing or diseases (2-4), although mechanistic evidence at the molecular level is lacking (5,6). 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 (7-9) 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., The mtDNAs of C57BL/6 and NZB/OlaHsd mice differ by 12 missense mutations, 4 transfer RNA (tRNA) mutations, 8 ribosomal RNA (rRNA) mutations, and 10 non-coding-region mutations (Extended Data Fig. 1b, [...]

Author(s): Ana Latorre-Pellicer; Raquel Moreno-Loshuertos; Ana Victoria Lechuga-Vieco; Ftima Snchez-Cabo; Carlos Torroja; Rebeca Acn-Prez; Enrique Calvo; Esther Aix; Andrs Gonzlez-Guerra; Angela Logan; Mara Luisa Bernad-Miana; Eduardo Romanos; Raquel Cruz; Sara [...]

It has been suggested that mitochondrial dysfunction and mtDNA variations may contribute to osteoarthritis (OA) pathogenesis. However, the causative link to support this claim is lacking. Here, we surgically-induced OA in conplastic mice in order to evaluate the functional consequences of mtDNA haplotypes in their joint degeneration. BL/6 NZB strain was developed with C57BL/6JOlaHsd nuclear genome and NZB/OlaHsdmtDNA while BL/6 C57 , which is the original, was developed with C57BL/6JOlaHsd nuclear genome and C57/OlaHsdmtDNA for comparison. The surgical DMM OA model was induced in both strains. Their knees were processed and examined for histopathological changes. Cartilage expression of markers of autophagy, apoptosis, oxidative stress and senescence were also analyzed by immunohistochemistry. The joints of BL/6 NZB mice that were operated presented more cellularity together with a reduced OARSI histopathology score, subchondral bone, menisci score and synovitis compared to those of BL/6 C57 mice. This was accompanied with higher autophagy and a lower apoptosis in the cartilage of BL/6 NZB mice that were operated. Therefore, the study demonstrates the functional impact of non-pathological variants of mtDNA on OA process using a surgically-induced OA model. Conplastic (BL/6 NZB ) mice develop less severe OA compared to the BL/6 C57 original strain. These findings demonstrate that mitochondria and mtDNA are critical targets for potential novel therapeutic approaches to treat osteoarthritis.

All metazoans depend on the consumption of O 2 by the mitochondrial oxidative phosphorylation system (OXPHOS) to produce energy. In addition, the OXPHOS uses O 2 to produce reactive oxygen species that can drive cell adaptations 1-4 , a phenomenon that occurs in hypoxia 4-8 and whose precise mechanism remains unknown. Ca 2+ is the best known ion that acts as a second messenger 9 , yet the role ascribed to Na + is to serve as a mere mediator of membrane potential 10 . Here we show that Na + acts as a second messenger that regulates OXPHOS function and the production of reactive oxygen species by modulating the fluidity of the inner mitochondrial membrane. A conformational shift in mitochondrial complex I during acute hypoxia 11 drives acidification of the matrix and the release of free Ca 2+ from calcium phosphate (CaP) precipitates. The concomitant activation of the mitochondrial Na + /Ca 2+ exchanger promotes the import of Na + into the matrix. Na + interacts with phospholipids, reducing inner mitochondrial membrane fluidity and the mobility of free ubiquinone between complex II and complex III, but not inside supercomplexes. As a consequence, superoxide is produced at complex III. The inhibition of Na + import through the Na + /Ca 2+ exchanger is sufficient to block this pathway, preventing adaptation to hypoxia. These results reveal that Na + controls OXPHOS function and redox signalling through an unexpected interaction with phospholipids, with profound consequences for cellular metabolism.