Prohibitin 1 is essential to preserve mitochondria and myelin integrity in Schwann cells

Abstract

In peripheral nerves, Schwann cells form myelin and provide trophic support to axons. We previously showed that the mitochondrial protein prohibitin 2 can localize to the axon-Schwann-cell interface and is required for developmental myelination. Whether the homologous protein prohibitin 1 has a similar role, and whether prohibitins also play important roles in Schwann cell mitochondria is unknown. Here, we show that deletion of prohibitin 1 in Schwann cells minimally perturbs development, but later triggers a severe demyelinating peripheral neuropathy. Moreover, mitochondria are heavily affected by ablation of prohibitin 1 and demyelination occurs preferentially in cells with apparent mitochondrial loss. Furthermore, in response to mitochondrial damage, Schwann cells trigger the integrated stress response, but, contrary to what was previously suggested, this response is not detrimental in this context. These results identify a role for prohibitin 1 in myelin integrity and advance our understanding about the Schwann cell response to mitochondrial damage.

The Mitochondrial Prohibitin (PHB) Complex in C. elegans Metabolism and Ageing Regulation

“…Interestingly, PHB depletion disrupts ER homeostasis, as assessed by a UPR ER stress reporter, suggesting deregulation in the interaction between mitochondria and ER [ 53 ]. A recent publication shows that mitochondrial dysfunction caused by PHB deficiency leads to ER stress in Schwann cells of conditional knockout mice [ 13 ]. Curiously, daf-2 mutants are protected against ER stress, which has been linked to its longevity phenotype [ 91 , 92 ].…”

“…Cardiac fatty acid oxidation (FAO) is impaired in short-lived PHB2 cardiac-specific knockout mice through downregulation of carnitine palmitoyltransferase, a rate-limiting enzyme in mitochondrial FAO, [ 116 ]. Moreover, PHB deficient Schwann cells show reduced biosynthesis of fatty acids [ 13 ]. It would be interesting to investigate if these mechanisms are conserved in the nematode and whether they might be differentially regulated in daf-2 mutants, which could explain the differential effect of PHB in gut LDs.…”

“…In mice, the post-natal tissue-specific absence of PHB in neurons results in neurodegeneration [ 10 ], and in β cells, PHB ablation impairs metabolic mitochondrial function and glucose homeostasis, leading to severe diabetes [ 11 ]. Furthermore, loss of PHB in podocytes results in kidney failure [ 12 ], and ablation in Schwann cells causes demyelinating neuropathy [ 13 ]. The mitochondrial phenotypes observed in these tissues and in mouse embryonic fibroblasts (MEFs), upon PHB ablation, include altered mitochondrial morphology, distribution, and dynamics, as well as aberrant cristae morphology [ 7 , 10 , 11 , 12 , 13 ].…”

“…Furthermore, loss of PHB in podocytes results in kidney failure [ 12 ], and ablation in Schwann cells causes demyelinating neuropathy [ 13 ]. The mitochondrial phenotypes observed in these tissues and in mouse embryonic fibroblasts (MEFs), upon PHB ablation, include altered mitochondrial morphology, distribution, and dynamics, as well as aberrant cristae morphology [ 7 , 10 , 11 , 12 , 13 ]. In the nematode C. elegans , the postembryonic RNAi depletion of the PHB complex affects mitochondrial ultrastructure in muscle cells [ 3 ].…”

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

“…Recently, mitochondria and cell metabolism were also implicated in myelin formation and maintenance in SCs. We reported that ablation of the primarily mitochondrial protein prohibitin 1 ( Phb1 ) in SCs greatly impairs myelin maintenance in the PNS ( Della-Flora Nunes et al, 2021 ). In addition, SC-specific deletion of the mitochondrial transcription factor Tfam ( Viader et al, 2011 ), the respiratory chain component Cox10 ( Fünfschilling et al, 2012 ), the metabolic regulator Lkb1 ( Beirowski et al, 2014 ; Pooya et al, 2014 ; Shen et al, 2014 ), the nicotinamide mononucleotide synthetizing enzyme Nampt ( Sasaki et al, 2018 ), or the nutrient-sensing O-linked N-acetylglucosamine transferase Ogt ( Kim et al, 2016 ), all lead to peripheral neuropathy phenotypes in mice.…”