PKC downregulation upon rapamycin treatment attenuates mitochondrial disease

Abstract

Leigh syndrome is a fatal neurometabolic disorder caused by defects in mitochondrial function. mTOR inhibition with rapamycin attenuates disease progression in a mouse model of Leigh syndrome (Ndufs4 KO mouse); however, the mechanism of rescue is unknown. Here we identify 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 signaling through both mTOR complexes, and reduces the abundance and activity of multiple protein kinase C (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. Reporting Summary Further information on research design is available in the Nature Research Reporting Summary linked to this article.

Leigh Syndrome: A Tale of Two Genomes

“…As discussed previously, studies on caloric restriction in yeast led to the idea that inhibition of mTORC1 can be used as therapy for mitochondrial disease. Rapamycin and its analogs are potent inhibitors of mTORC1 and have been shown to improve symptoms in some patients with mitochondrial disease ( Sage-Schwaede et al, 2019 ; Martin-Perez et al, 2020 ). The effect of rapamycin has been tested in NDUFS4 KO mice, with results from this and other studies showing that mTORC1 inhibition alleviated mitochondrial disease in the mouse model of LS ( Johnson et al, 2013 ; Cheema et al, 2021 ).…”

mTORC2: The other mTOR in autophagy regulation

“…PKCα has been shown to suppress autophagy in breast cancer cells (Wong et al, 2017 ) and during gestational diabetes, where its action may trigger neural tube defects (Wang et al, 2017 ). Rapamycin treatment, and resulting inhibition of mTORC2, reduced the phosphorylation and activity of several PKC isozymes, in particular PKCβ, and ameliorated mitochondrial disease and neuropathology in a mouse model of Leigh syndrome (Martin‐Perez et al, 2020 ). PKCβ pharmacological inhibition or genetic depletion increased autophagy and mitochondrial health (Patergnani et al, 2013 ).…”

Accessory Subunits of the Matrix Arm of Mitochondrial Complex I with a Focus on Subunit NDUFS4 and Its Role in Complex I Function and Assembly

“…mTOR is present in two distinct complexes, mTORC1 and mTORC2. mTORC2 was initially described as rapamycin insensitive; however, chronic rapamycin treatment is thought to decrease the formation of new functional mTORC2 [90], resulting in a decrease of PKC-β-dependent pro-inflammatory signaling [91]. Rapamycin treatment thus exerts its positive effect via the inhibition of both mTORC complexes, resulting in changes in metabolism and a decreased tendency to inflammation.…”