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J Am Soc Nephrol. 2019 Jul;30(7):1174-1191. doi: 10.1681/ASN.2018111117. Epub 2019 May 24.

Bif-1 Interacts with Prohibitin-2 to Regulate Mitochondrial Inner Membrane during Cell Stress and Apoptosis.

Author information

1
Department of Cellular Biology and Anatomy.
2
Vascular Biology Center.
3
Department of Biochemistry and Molecular Biology.
4
Cancer Center, and.
5
Department of Physiology, Medical College of Georgia, Augusta University, Augusta, Georgia.
6
Department of Biological Sciences, University of Texas at El Paso, El Paso, Texas.
7
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
8
Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania; and.
9
Department of Cellular Biology and Anatomy, zdong@augusta.edu.
10
Medical Research Line, Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia.

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.

KEYWORDS:

apoptosis; mitochondria; renal ischemia

PMID:
31126972
DOI:
10.1681/ASN.2018111117

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