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OMA1 mediates local and global stress responses against protein misfolding in CHCHD10 mitochondrial myopathy
Mario K. Shammas, … , Joanna Poulton, Derek P. Narendra
Mario K. Shammas, … , Joanna Poulton, Derek P. Narendra
Published June 14, 2022
Citation Information: J Clin Invest. 2022;132(14):e157504. https://doi.org/10.1172/JCI157504.
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Research Article Cell biology Genetics Article has an altmetric score of 1

OMA1 mediates local and global stress responses against protein misfolding in CHCHD10 mitochondrial myopathy

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Abstract

Mitochondrial stress triggers a response in the cell’s mitochondria and nucleus, but how these stress responses are coordinated in vivo is poorly understood. Here, we characterize a family with myopathy caused by a dominant p.G58R mutation in the mitochondrial protein CHCHD10. To understand the disease etiology, we developed a knockin (KI) mouse model and found that mutant CHCHD10 aggregated in affected tissues, applying a toxic protein stress to the inner mitochondrial membrane. Unexpectedly, the survival of CHCHD10-KI mice depended on a protective stress response mediated by the mitochondrial metalloendopeptidase OMA1. The OMA1 stress response acted both locally within mitochondria, causing mitochondrial fragmentation, and signaled outside the mitochondria, activating the integrated stress response through cleavage of DAP3-binding cell death enhancer 1 (DELE1). We additionally identified an isoform switch in the terminal complex of the electron transport chain as a component of this response. Our results demonstrate that OMA1 was critical for neonatal survival conditionally in the setting of inner mitochondrial membrane stress, coordinating local and global stress responses to reshape the mitochondrial network and proteome.

Authors

Mario K. Shammas, Xiaoping Huang, Beverly P. Wu, Evelyn Fessler, Insung Y. Song, Nicholas P. Randolph, Yan Li, Christopher K.E. Bleck, Danielle A. Springer, Carl Fratter, Ines A. Barbosa, Andrew F. Powers, Pedro M. Quirós, Carlos Lopez-Otin, Lucas T. Jae, Joanna Poulton, Derek P. Narendra

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Figure 2

The C10 G58 position is highly conserved and lies on an insolubility-prone face of the α-helix.

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The C10 G58 position is highly conserved and lies on an insolubility-pro...
(A) Top: Amino acid sequence of the hydrophobic α-helix of C10 showing pathogenic variants and highlighting the GXXXG motif. Bottom: EVfold prediction of the structure of the α-helix. (B) EVcouplings conservation analysis of C10 and predicted hydrophobicity of the region around the α-helix. (C) Levels of insoluble/total C10 in HEK293 C2/C10-DKO cells after transfection with C10 containing G58 substitutions with amino acids of varying hydrophobicity on the Kyte-Doolittle scale (x axis) (n = 3 biological replicates). (D) Representative Airyscan images of mitochondria in HeLa cells transfected with C10 containing the indicated G58 substitutions. Scale bar: 10 μm. Original magnification, ×5 (bottom images). Plot shows quantification of mitochondrial (Mito) fragmentation in HeLa cells transfected with C10 containing G58 substitutions with amino acids of varying hydrophobicity (n ≥50 cells per replicate from 3 biological replicates; individual data points are shown in Supplemental Figure 4B). (E) Representative blot of a Triton X–soluble/–insoluble (TX-soluble/-insoluble) assay of HEK293 C2/C10-DKO cells transfected with C10, whereby individual residues of the α-helix were mutated to valines. Graph shows quantification of the blots (n = 3–4 biological replicates). Error bars represent the SEM. **P < 0.01 and ****P < 0.0001, by 1-way ANOVA with Dunnett’s T3 multiple comparisons with pooled variance (D) or Sidak’s multiple comparisons (E). See also Supplemental Figure 4.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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