Mitochondrial stress in liver function and dysfunction - Project Summary The liver is responsible for the multitude of processes, notably the metabolic homeostasis and detoxification. Mitochondria are critical for the metabolic function of the liver and, thus, mitochondrial dysfunction is a major cause for liver diseases. As the liver is constantly exposed to harmful substances from metabolism and drug processing, liver mitochondria are especially susceptible to functional impairment. We propose that maintaining functional mitochondria under the stressful environment will be a key to the long-term preservation of liver health. The mitochondrial fusion protein optic atrophy 1 (OPA1) is essential for proper function of mitochondria, and the OPA1 gene knockout (KO) in major organs impairs mitochondrial energetics and causes animal death. However, we observed that, despite the important role of mitochondria in the liver, liver-specific OPA1-KO mice are healthy and maintain normal mitochondrial and liver functions. Liver is a resilient organ that has high regenerative capacity after injury. While OPA1-KO livers do not show any injury, we found that OPA1 KO induces a robust and efficient integrated stress response (ISR) to preserve liver function, indicating that the ISR is another mechanism of liver resiliency. These observations suggest that the liver successfully handles the stress induced by OPA1 KO, providing the important experimental system for mechanistic understanding of the ISR as the mechanism of liver resiliency. In this proposal, we will elucidate the OPA1 function in the liver, define the mechanism of how liver handles the mitochondrial stress evoked by the lack of OPA1 function, and test the feasibility of utilizing the liver ISR for a protective strategy in drug-induced liver injury. Our preliminary data indicate that the liver has a unique mechanism for ISR through a novel regulation of the critical transcription factor ATF4. We also discovered a new role of OPA1 as an assembly factor for respiratory complex V, and found that accumulation of assembly intermediates of complex V evokes mitochondrial stress for the ISR induction. In this proposal, therefore, we will test our Central Hypothesis that OPA1 is a novel assembly factor for the respiratory complex V, and its absence in the liver induces the ISR, which prevents liver injury and serves as a mechanism of the liver resiliency. We will test this hypothesis by three specific aims: (1) to define the unique mechanism regulating ATF4 in the liver ISR induced by OPA1 KO, (2) to elucidate the new role of OPA1 as a complex V assembly factor, and (3) to test the liver ISR as a mechanism of liver resiliency by using the acetaminophen overdose as a model for drug-induced liver injury. Completion of the proposed studies will generate a new paradigm for the mechanisms of the liver ISR and OPA1 function, and provide scientific basis for a new therapeutic strategy to decrease liver diseases.
