RT Journal Article SR Electronic T1 Oxidative phosphorylation is a pivotal therapeutic target of fibrodysplasia ossificans progressiva JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e202302219 DO 10.26508/lsa.202302219 VO 7 IS 5 A1 Sun, Liping A1 Jin, Yonghui A1 Nishio, Megumi A1 Watanabe, Makoto A1 Kamakura, Takeshi A1 Nagata, Sanae A1 Fukuda, Masayuki A1 Maekawa, Hirotsugu A1 Kawai, Shunsuke A1 Yamamoto, Takuya A1 Toguchida, Junya YR 2024 UL https://www.life-science-alliance.org/content/7/5/e202302219.abstract AB Heterotopic ossification (HO) is a non-physiological bone formation where soft tissue progenitor cells differentiate into chondrogenic cells. In fibrodysplasia ossificans progressiva (FOP), a rare genetic disease characterized by progressive and systemic HO, the Activin A/mutated ACVR1/mTORC1 cascade induces HO in progenitors in muscle tissues. The relevant biological processes aberrantly regulated by activated mTORC1 remain unclear, however. RNA-sequencing analyses revealed the enrichment of genes involved in oxidative phosphorylation (OXPHOS) during Activin A–induced chondrogenesis of mesenchymal stem cells derived from FOP patient–specific induced pluripotent stem cells. Functional analyses showed a metabolic transition from glycolysis to OXPHOS during chondrogenesis, along with increased mitochondrial biogenesis. mTORC1 inhibition by rapamycin suppressed OXPHOS, whereas OXPHOS inhibitor IACS-010759 inhibited cartilage matrix formation in vitro, indicating that OXPHOS is principally involved in mTORC1-induced chondrogenesis. Furthermore, IACS-010759 inhibited the muscle injury–induced enrichment of fibro/adipogenic progenitor genes and HO in transgenic mice carrying the mutated human ACVR1. These data indicated that OXPHOS is a critical downstream mediator of mTORC1 signaling in chondrogenesis and therefore is a potential FOP therapeutic target.