PKC downregulation upon rapamycin treatment attenuates mitochondrial disease
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Date
2020-12
Authors
Martin-Perez, Miguel
Grillo, Anthony S.
Ito, Takashi K.
Valente, Anthony S.
Han, Jeehae
Entwisle, Samuel W.
Huang, Heather Z.
Kim, Dayae
Yajima, Masanao
Kaeberlein, Matt
Version
Accepted manuscript
OA Version
Citation
M. Martin-Perez, A.S. Grillo, T.K. Ito, A.S. Valente, J. Han, S.W. Entwisle, H.Z. Huang, D. Kim, M. Yajima, M. Kaeberlein, J. Villén. 2020. "PKC downregulation upon rapamycin treatment attenuates mitochondrial disease.." Nat Metab, Volume 2, Issue 12, pp. 1472 - 1481. https://doi.org/10.1038/s42255-020-00319-x
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.
Description
Published in final edited form as:
Nat Metab. 2020 December ; 2(12): 1472–1481. doi:10.1038/s42255-020-00319-x.