PKC downregulation upon rapamycin treatment attenuates mitochondrial disease

Published in final edited form as: Nat Metab. 2020 December ; 2(12): 1472–1481. doi:10.1038/s42255-020-00319-x.Leigh syndrome is a fatal neurometabolic disorder caused by defects in mitochondrial function. Mechanistic target of rapamycin (mTOR) inhibition with rapamycin attenuates disease progression in a mouse model of Leigh syndrome (Ndufs4 knock-out (KO) mouse); however, the mechanism of rescue is unknown. Here we identify protein kinase C (PKC) downregulation as a key event mediating the beneficial effects of rapamycin treatment of Ndufs4 KO mice. Assessing the impact of rapamycin on the brain proteome and phosphoproteome of Ndufs4 KO mice, we find that rapamycin restores mitochondrial protein levels, inhibits signalling through both mTOR complexes and reduces the abundance and activity of multiple PKC isoforms. Administration of PKC inhibitors increases survival, delays neurological deficits, prevents hair loss and decreases inflammation in Ndufs4 KO mice. Thus, PKC may be a viable therapeutic target for treating severe mitochondrial disease.R01 NS098329 - NINDS NIH HHS; T32 HG00035 - U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI); T32 LM012419 - NLM NIH HHS; T32 HG000035 - NHGRI NIH HHS; R35 GM119536 - NIGMS NIH HHS; F32 NS110109 - NINDS NIH HHS; postdoctoral fellowship - Uehara Memorial Foundation; P30 AG013280 - NIA NIH HHS; postdoctoral fellowship - MEXT | Japan Society for the Promotion of Science (JSPS)Accepted manuscrip