The short variant of optic atrophy 1 (OPA1) improves cell survival under oxidative stress.

Abstract

Optic atrophy 1 (OPA1) is a dynamin protein that mediates mitochondrial fusion at the inner membrane. OPA1 is also necessary for maintaining the cristae and thus essential for supporting cellular energetics. OPA1 exists as membrane-anchored long form (L-OPA1) and short form (S-OPA1) that lacks the transmembrane region and is generated by cleavage of L-OPA1. Mitochondrial dysfunction and cellular stresses activate the inner membrane-associated zinc metallopeptidase OMA1 that cleaves L-OPA1, causing S-OPA1 accumulation. The prevailing notion has been that L-OPA1 is the functional form, whereas S-OPA1 is an inactive cleavage product in mammals, and that stress-induced OPA1 cleavage causes mitochondrial fragmentation and sensitizes cells to death. However, S-OPA1 contains all functional domains of dynamin proteins, suggesting that it has a physiological role. Indeed, we recently demonstrated that S-OPA1 can maintain cristae and energetics through its GTPase activity, despite lacking fusion activity. Here, applying oxidant insult that induces OPA1 cleavage, we show that cells unable to generate S-OPA1 are more sensitive to this stress under obligatory respiratory conditions, leading to necrotic death. These findings indicate that L-OPA1 and S-OPA1 differ in maintaining mitochondrial function. Mechanistically, we found that cells that exclusively express L-OPA1 generate more superoxide and are more sensitive to Ca2+-induced mitochondrial permeability transition, suggesting that S-OPA1, and not L-OPA1, protects against cellular stress. Importantly, silencing of OMA1 expression increased oxidant-induced cell death, indicating that stress-induced OPA1 cleavage supports cell survival. Our findings suggest that S-OPA1 generation by OPA1 cleavage is a survival mechanism in stressed cells.

• Authors: Hakjoo Lee, Sylvia B Smith, Shey-Shing Sheu, Yisang Yoon
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 295 Issue 19 Pg. 6543-6560 (05 08 2020) ISSN: 1083-351X [Electronic] United States
• PMID: 32245890 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Lee et al.

Chemical References

• Isoenzymes
• Superoxides
• GTP Phosphohydrolases
• Opa1 protein, mouse
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Cell Line
• Cell Survival
• GTP Phosphohydrolases (genetics, metabolism)
• Isoenzymes (genetics, metabolism)
• Mice
• Mice, Knockout
• Mitochondria (genetics, metabolism)
• Mitochondrial Membranes (enzymology)
• Oxidative Stress
• Permeability
• Superoxides (metabolism)