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

• Type of Material: Article
• Authors: Hakjoo Lee, Augusta University; Tae Jin Lee, Augusta University; Chad A. Galloway, University of Rochester; Wenbo Zhi, Augusta University; Wei Xiao, Augusta University; Karen L. de Mesy Bentley, University of Rochester; Ashok Sharma, Augusta University; Yong Teng, Emory University; Hiromi Sesaki, Johns Hopkins University; Yisang Yoon, Augusta University
• Language: English
• Date: 2023-10-23
• Publisher: Springer Nature
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2023
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.1038%2Fs41467-023-42564-0
• Title of Journal or Parent Work: Nature Communications
• Volume: 14
• Start Page: 6721
• Grant/Funding Information: This work was supported by NIH HL093671, EY031483 and DK136753 to YY, GM144103 to HS, DE028351 and DE032084 to YT.
• Keywords: Energy metabolism; Mechanisms of disease; Mitochondria; Hepatocytes
• Research Categories: Biology, Cell

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.