Activation of mTORC1 and c-Jun by Prohibitin1 loss in Schwann cells may link mitochondrial dysfunction to demyelination

• Published in: eLife Vol. 10
• Main Authors: Della-Flora Nunes, Gustavo, Wilson, Emma R, Hurley, Edward, He, Bin, O'Malley, Bert W, Poitelon, Yannick, Wrabetz, Lawrence, Feltri, M Laura
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 14.09.2021; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Animals; c-Jun protein; Demyelinating diseases; Demyelinating Diseases - metabolism; Demyelinating Diseases - pathology; Demyelination; Genotype & phenotype; Kinases; Lipids; mechanistic target of rapamycin; Mechanistic Target of Rapamycin Complex 1 - metabolism; Metabolism; Mice; Mice, Knockout; Mitochondria; Mitochondria - metabolism; mitochondrial stress response; Myelin; myelin maintenance; Myelin proteins; Myelin Sheath - metabolism; Nervous system; Neuroscience; Peripheral neuropathy; PHB1; Phosphorylation; Physiological aspects; Physiological research; Prohibitin; Prohibitins; Proteins; Proto-Oncogene Proteins c-jun - metabolism; Rapamycin; Repressor Proteins - genetics; Schwann cells; Schwann Cells - enzymology; Schwann Cells - metabolism; Transcription factors; Up-Regulation; United States; mouse; PHB1; mitochondrial stress response; demyelination; neuroscience; schwann cells; myelin maintenance; mechanistic target of rapamycin
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.66278

Schwann cell (SC) mitochondria are quickly emerging as an important regulator of myelin maintenance in the peripheral nervous system (PNS). However, the mechanisms underlying demyelination in the context of mitochondrial dysfunction in the PNS are incompletely understood. We recently showed that conditional ablation of the mitochondrial protein Prohibitin 1 (PHB1) in SCs causes a severe and fast progressing demyelinating peripheral neuropathy in mice, but the mechanism that causes failure of myelin maintenance remained unknown. Here, we report that mTORC1 and c-Jun are continuously activated in the absence of , likely as part of the SC response to mitochondrial damage. Moreover, we demonstrate that these pathways are involved in the demyelination process, and that inhibition of mTORC1 using rapamycin partially rescues the demyelinating pathology. Therefore, we propose that mTORC1 and c-Jun may play a critical role as executioners of demyelination in the context of perturbations to SC mitochondria.