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PKC downregulation upon rapamycin treatment attenuates mitochondrial disease.

Authors :
Martin-Perez M
Grillo AS
Ito TK
Valente AS
Han J
Entwisle SW
Huang HZ
Kim D
Yajima M
Kaeberlein M
Villén J
Source :
Nature metabolism [Nat Metab] 2020 Dec; Vol. 2 (12), pp. 1472-1481. Date of Electronic Publication: 2020 Dec 14.
Publication Year :
2020

Abstract

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.

Details

Language :
English
ISSN :
2522-5812
Volume :
2
Issue :
12
Database :
MEDLINE
Journal :
Nature metabolism
Publication Type :
Academic Journal
Accession number :
33324011
Full Text :
https://doi.org/10.1038/s42255-020-00319-x