TY - JOUR
T1 - Prohibitin 1 is essential to preserve mitochondria and myelin integrity in Schwann cells
AU - Della-Flora Nunes, Gustavo
AU - Wilson, Emma R.
AU - Marziali, Leandro N.
AU - Hurley, Edward
AU - Silvestri, Nicholas
AU - He, Bin
AU - O’Malley, Bert W.
AU - Beirowski, Bogdan
AU - Poitelon, Yannick
AU - Wrabetz, Lawrence
AU - Feltri, M. Laura
N1 - Funding Information:
We thank J. Catlin and S. S. Rasam for assistance in performing the UPRmt western blot and lipid peroxidation (TBARS) experiments, respectively. We thank M. R. Weaver for the careful English Language revision. This work was funded by grant NIH-NINDS-R01NS100464 (to M.L.F.). Generation of the Phb1-floxed animals was originally supported by National Institutes of Health Grants HD08818 and HD07857 to B.W.O.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/6/2
Y1 - 2021/6/2
N2 - 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.
AB - 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.
KW - Animals
KW - Aspartate-Ammonia Ligase/genetics
KW - Axons/metabolism
KW - Eukaryotic Initiation Factor-2/genetics
KW - Female
KW - Femoral Nerve/metabolism
KW - Heat-Shock Proteins/genetics
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Transgenic
KW - Mitochondria/metabolism
KW - Myelin Sheath/metabolism
KW - Phosphoenolpyruvate Carboxykinase (ATP)/genetics
KW - Protein Isoforms/genetics
KW - RNA, Messenger/genetics
KW - Repressor Proteins/deficiency
KW - Schwann Cells/metabolism
KW - Sciatic Nerve/metabolism
KW - Stress, Physiological
KW - Tibial Nerve/metabolism
KW - Transcription Factor CHOP/genetics
KW - X-Box Binding Protein 1/genetics
KW - gamma-Glutamylcyclotransferase/genetics
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U2 - 10.1038/s41467-021-23552-8
DO - 10.1038/s41467-021-23552-8
M3 - Article
C2 - 34078899
AN - SCOPUS:85107133862
VL - 12
JO - Nat Commun
JF - Nat Commun
SN - 2041-1723
IS - 1
M1 - 3285
ER -