RT Journal Article
SR Electronic
T1 OMA1 mediates local and global stress responses against protein misfolding in CHCHD10 mitochondrial myopathy
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.12.21.473493
DO 10.1101/2021.12.21.473493
A1 Mario K. Shammas
A1 Xiaoping Huang
A1 Beverly P. Wu
A1 Insung Song
A1 Nicholas Randolph
A1 Yan Li
A1 Christopher K. E. Bleck
A1 Danielle A. Springer
A1 Carl Fratter
A1 Ines A. Barbosa
A1 Andrew F. Powers
A1 Pedro M. Quirós
A1 Carlos Lopez-Otin
A1 Joanna Poulton
A1 Derek P. Narendra
YR 2021
UL http://biorxiv.org/content/early/2021/12/21/2021.12.21.473493.abstract
AB 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 novel knock-in mouse model and found that mutant CHCHD10 aggregates in affected tissues, applying a toxic protein stress to the inner mitochondrial membrane. Unexpectedly, survival of CHCHD10 knock-in mice depended on a protective stress response mediated by OMA1. The OMA1 stress response acted both locally within mitochondria, inhibiting mitochondrial fusion, and signaled outside the mitochondria, activating the integrated stress response. We additionally identified an isoform switch in the terminal complex of the electron transport chain as a novel component of this response. Our results demonstrate that OMA1 is essential 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.Competing Interest StatementThe authors have declared no competing interest.