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Longevity is regulated by a network of closely linked metabolic systems. We used a combination of mouse population genetics and RNA interference in Caenorhabditis elegans to identify mitochondrial ribosomal protein S5 (Mrps5) and other mitochondrial ribosomal proteins as metabolic and longevity regulators. MRP knockdown triggers mitonuclear protein imbalance, reducing mitochondrial respiration and activating the mitochondrial unfolded protein response. Specific antibiotics targeting mitochondrial translation and ethidium bromide (which impairs mitochondrial DNA transcription) pharmacologically mimic mrp knockdown and extend worm lifespan by inducing mitonuclear protein imbalance, a stoichiometric imbalance between nuclear and mitochondrially encoded proteins. This mechanism was also conserved in mammalian cells. In addition, resveratrol and rapamycin, longevity compounds acting on different molecular targets, similarly induced mitonuclear protein imbalance, the mitochondrial unfolded protein response and lifespan extension in C. elegans. Collectively these data demonstrate that MRPs represent an evolutionarily conserved protein family that ties the mitochondrial ribosome and mitonuclear protein imbalance to the mitochondrial unfolded protein response, an overarching longevity pathway across many species.
Longevity is coordinated by intersecting pathways, often converging on metabolic networks1-4. A key player in lifespan regulation is the mitochondrion. Over a thousand proteins encoded by nuclear DNA (nDNA) translocate to and function in mitochondria5, in synchrony with 13 proteins encoded by the mitochondrial DNA (mtDNA) that require a separate translationmachinery, includingmitochondrial ribosomal proteins (MRPs)6,7. Many molecular studies of longevity have exploited simple organisms and loss- or gain-of-function mutations, but the complex connectedness of mitochondrial and metabolic longevity networks benefits from an integrative cross-species approach2.
Here we pioneered such a strategy and used the BXD reference population of mice2,8-10 to identify mitochondrial ribosomal protein S5 (Mrps5) and other members of the MRP family as longevity genes. In C. elegans, we confirmed this role of MRPs and demonstrated that they induce a stoichiometric imbalance between nDNA- and mtDNA-encoded oxidative phosphorylation proteins, hereafter termed 'mitonuclear protein imbalance', which activates the mitochondrial unfolded protein response (UPRmt). Our conclusions were corroborated using specific antibiotics targeting bacterial/mitochondrial translation, and ethidium bromide, which inhibits mtDNA transcription. This mechanism is shared with pathways that induce mitonuclear protein imbalance from a nuclear perspective, such as the UPRmt and lifespan enhancing effects of rapamycin and resveratrol.Our data hence tie mitochondrial translation and metabolism to natural lifespan regulation across species.
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