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

Author:

Lee HakjooORCID,Lee Tae JinORCID,Galloway Chad A.ORCID,Zhi Wenbo,Xiao Wei,de Mesy Bentley Karen L.ORCID,Sharma AshokORCID,Teng YongORCID,Sesaki Hiromi,Yoon YisangORCID

Abstract

AbstractMitochondria 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.

Funder

U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute

U.S. Department of Health & Human Services | NIH | National Eye Institute

U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases

U.S. Department of Health & Human Services | NIH | National Institute of Dental and Craniofacial Research

U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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