OPA1 controls mitochondrial dysfunction-driven liver fibrosis in MASLD

Progressive hepatic fibrosis is the principal determinant of morbidity and mortality in metabolic dysfunction-associated steatotic liver disease and steatohepatitis (MASLD/MASH). Mitochondrial dysfunction is a hallmark of MASH, and injured hepatocytes can release mitochondrial damage-associated molecular patterns (mito-DAMPs) that promote fibrosis, but how mitochondrial dynamics and quality control shape the fibrotic response in MASLD/MASH has remained unclear.

To address this, researchers performed large-scale genomic analyses of mitochondrial genes governing mitophagy, fusion, and fission in human MASLD, using a power-equivalent sample size of approximately 700,000 individuals.

They identified a strong association between hepatic fibrosis and the mitochondrial fusion factor dynamin-like GTPase optic atrophy 1 (OPA1). OPA1 transcript and protein abundance in the liver epithelium became progressively dysregulated with advancing fibrosis.

In mice, hepatocyte-specific OPA1 loss alone was sufficient to induce hepatic stellate cell activation and fibrosis in zone 3. It also promoted the release of mito-DAMPs into the circulation and exacerbated fibrosis in experimental MASH.

The findings identify OPA1 as a central regulator of the hepatic fibrotic response and connect defective mitochondrial homeostasis to mito-DAMP release, hepatic stellate cell activation, and fibrosis in MASLD.