OMA1 protects from liver injury and tumorigenesis during aging by controlling hepatic immunogenicity.

Abstract

Hepatic inflammation and immunosurveillance play major roles in the progression of liver cancer. A common trigger for hepatic inflammation is oxidative stress, which stems from mitochondrial dysfunction. Here, we demonstrate that deletion of the mitochondrial stress integrator OMA1 increases hepatic primary tumor incidence and impairs survival in mice. Persistent activation of the KEAP1-Nrf2 oxidative stress pathway in the absence of OMA1 promotes early liver injury, which progresses into chronic hepatic inflammation and fibrosis during aging. Exhausted CD8 and CD4 T cells gradually accumulate in Oma1 livers, facilitating hepatic tumor progression. Adoptive transfer and bone marrow-transplant experiments indicate that hepatic immunogenicity increases in the absence of parenchymal OMA1. Furthermore, hepatocyte-specific Oma1 deletion is sufficient to trigger NRF2 signaling, hepatocyte death, and immune exhaustion, suggesting that immunosurveillance during liver aging relies on the hepatic expression of OMA1. Given the therapeutic interest of OMA1 in several pathologies, these data are crucial to guide the generation of safe OMA1-targeted therapies.