The mitochondrial fusion protein OPA1 is dispensable in the liver and its absence induces mitohormesis to protect liver from drug-induced injury

Hakjoo Lee, Tae Jin Lee, Chad A. Galloway, Wenbo Zhi, Wei Xiao, Karen L. de Mesy Bentley, Ashok Sharma, Yong Teng, Hiromi Sesaki and Yisang Yoon ()
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Hakjoo Lee: Augusta University
Tae Jin Lee: Medical College of Georgia, Augusta University
Chad A. Galloway: University of Rochester Medical Center
Wenbo Zhi: Medical College of Georgia, Augusta University
Wei Xiao: Medical College of Georgia, Augusta University
Karen L. de Mesy Bentley: University of Rochester Medical Center
Ashok Sharma: Medical College of Georgia, Augusta University
Yong Teng: Emory University School of Medicine
Hiromi Sesaki: Johns Hopkins University School of Medicine
Yisang Yoon: Augusta University

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract Mitochondria are critical for metabolic homeostasis of the liver, and their dysfunction is a major cause of liver diseases. Optic atrophy 1 (OPA1) is a mitochondrial fusion protein with a role in cristae shaping. Disruption of OPA1 causes mitochondrial dysfunction. However, the role of OPA1 in liver function is poorly understood. In this study, we delete OPA1 in the fully developed liver of male mice. Unexpectedly, OPA1 liver knockout (LKO) mice are healthy with unaffected mitochondrial respiration, despite disrupted cristae morphology. OPA1 LKO induces a stress response that establishes a new homeostatic state for sustained liver function. Our data show that OPA1 is required for proper complex V assembly and that OPA1 LKO protects the liver from drug toxicity. Mechanistically, OPA1 LKO decreases toxic drug metabolism and confers resistance to the mitochondrial permeability transition. This study demonstrates that OPA1 is dispensable in the liver, and that the mitohormesis induced by OPA1 LKO prevents liver injury and contributes to liver resiliency.

Date: 2023
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DOI: 10.1038/s41467-023-42564-0

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