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.
Highlights
IntroductionSchwann cells form myelin and provide trophic support to axons
In peripheral nerves, Schwann cells form myelin and provide trophic support to axons
We investigated the role of PHB1 in Schwann cells (SCs) using conditional knockout mice
Summary
Schwann cells form myelin and provide trophic support to axons. Mitochondria, which are pivotal organelles in cellular metabolism, are quickly emerging as important regulators of myelin formation and maintenance in SCs. Peripheral neuropathy is a common manifestation of genetic mitochondrial disorders, affecting about 30% of all patients[3]. PHB2 associates with the homologous protein PHB1, forming a large oligomeric ring-like structure in the inner mitochondrial membrane[10] This structure is thought to act as a platform that aids in the regulation of several aspects of mitochondrial biogenesis, dynamics, and metabolism[9,11]. We show that, contrary to deletion of Phb[2], deletion of Phb[1] in SCs causes only a minimal developmental phenotype, but triggers a severe demyelinating peripheral neuropathy after myelination is completed. These results advance our understanding of how SCs respond to mitochondrial damage, solidify the importance of SC mitochondria to maintain nerve homeostasis, and reveal that, unexpectedly, PHB1 and PHB2 may have some independent functions
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