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Here we show that, in mice with impaired mtRC in cartilage, reductive\/reverse TCA cycle segments are activated to produce metabolite-derived amino acids and stimulate biosynthesis processes by mechanistic target of rapamycin complex 1 (mTORC1) activation during a period of massive skeletal growth and biomass production. However, chronic hyperactivation of mTORC1 suppresses autophagy-mediated organelle recycling and disturbs extracellular matrix secretion to trigger chondrocytes death, which is ameliorated by targeting the reductive metabolism. These findings explain how a primarily beneficial metabolic adaptation response required to counterbalance the loss of mtRC function, eventually translates into profound cell death and cartilage tissue degeneration. The knowledge of these dysregulated key nutrient signaling pathways can be used to target skeletal aging in mitochondrial disease.<\/jats:p>","DOI":"10.1126\/sciadv.ads1842","type":"journal-article","created":{"date-parts":[[2025,4,18]],"date-time":"2025-04-18T13:58:46Z","timestamp":1744984726000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":13,"title":["Metabolic rewiring caused by mitochondrial dysfunction promotes mTORC1-dependent skeletal aging"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8457-0566","authenticated-orcid":true,"given":"Kristina","family":"Bubb","sequence":"first","affiliation":[{"name":"Department of Pediatrics and Adolescent Medicine, Experimental Neonatology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, 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