Bif-1 interacts with prohibitin-2 to regulate mitochondrial inner membrane during cell stress and apoptosis

Sung Gyu Cho, Xiao Xiao, Shixuan Wang, Hua Gao, Ruslan Rafikov, Stephen Black, Shang Huang, Han Fei Ding, Yisang Yoon, Robert A. Kirken, Xiao Ming Yin, Hong Gang Wang, Zheng Dong

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Background Mitochondria are dynamic organelles that undergo fission and fusion. During cell stress, mitochondrial dynamics shift to fission, leading to mitochondrial fragmentation, membrane leakage, and apoptosis. Mitochondrial fragmentation requires the cleavage of both outer and inner membranes, but the mechanism of inner membrane cleavage is unclear. Bif-1 and prohibitin-2 may regulate mitochondrial dynamics. Methods We used azide-induced ATP depletion to incite cell stress in mouse embryonic fibroblasts and renal proximal tubular cells, and renal ischemia-reperfusion to induce stress in mice. We also used knockout cells and mice to determine the role of Bif-1, and used multiple techniques to analyze the molecular interaction between Bif-1 and prohibitin-2. Results Upon cell stress, Bif-1 translocated to mitochondria to bind prohibitin-2, resulting in the disruption of prohibitin complex and proteolytic inactivation of the inner membrane fusion protein OPA1. Bif-1-deficiency inhibited prohibitin complex disruption, OPA1 proteolysis, mitochondrial fragmentation, and apoptosis. Domain deletion analysis indicated that Bif-1 interacted with prohibitin-2 via its C-terminus. Notably, mutation of Bif-1 at its C-terminal tryptophan-344 not only prevented Bif-1/prohibitin-2 interaction but also reduced prohibitin complex disruption, OPA1 proteolysis, mitochondrial fragmentation, and apoptosis, supporting a pathogenic role of Bif-1/prohibitin-2 interaction. In mice, Bif-1 bound prohibitin-2 during renal ischemia/reperfusion injury, and Bif-1-deficiency protected against OPA1 proteolysis, mitochondrial fragmentation, apoptosis and kidney injury. Conclusions These findings suggest that during cell stress, Bif-1 regulates mitochondrial inner membrane by interacting with prohibitin-2 to disrupt prohibitin complexes and induce OPA1 proteolysis and inactivation.

Original languageEnglish (US)
Pages (from-to)1174-1191
Number of pages18
JournalJournal of the American Society of Nephrology
Volume30
Issue number7
DOIs
StatePublished - Jul 2019

All Science Journal Classification (ASJC) codes

  • Nephrology

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    Cho, S. G., Xiao, X., Wang, S., Gao, H., Rafikov, R., Black, S., Huang, S., Ding, H. F., Yoon, Y., Kirken, R. A., Yin, X. M., Wang, H. G., & Dong, Z. (2019). Bif-1 interacts with prohibitin-2 to regulate mitochondrial inner membrane during cell stress and apoptosis. Journal of the American Society of Nephrology, 30(7), 1174-1191. https://doi.org/10.1681/ASN.2018111117