Hepatocyte mitochondria-derived danger signals directly activate hepatic stellate cells and drive progression of liver fibrosis

TLDR

Mitochondria, owing to their bacterial ancestry, release damage‑associated molecular patterns (mito‑DAMPs) upon injury that provoke inflammation, yet their contribution to fibrosis remains unclear. The study investigates whether mito‑DAMPs released from injured hepatocytes activate hepatic stellate cells and drive fibrosis, and whether targeting their release or macrophage phagocytosis could serve as an antifibrotic strategy. In a mouse strain system, mito‑DAMPs—primarily mtDNA—from injured hepatocyte mitochondria activate hepatic stellate cells and drive scarring, with release regulated by efferocytosis of dying hepatocytes by resident macrophages and infiltrating Gr‑1(+) myeloid cells. Human NASH patients with fibrosis exhibit markedly elevated circulating mito‑DAMPs, confirming the identified pathway and suggesting diagnostic and therapeutic potential.

Abstract

Due to their bacterial ancestry, many components of mitochondria share structural similarities with bacteria. Release of molecular danger signals from injured cell mitochondria (mitochondria-derived damage-associated molecular patterns, mito-DAMPs) triggers a potent inflammatory response, but their role in fibrosis is unknown. Using liver fibrosis resistant/susceptible mouse strain system, we demonstrate that mito-DAMPs released from injured hepatocyte mitochondria (with mtDNA as major active component) directly activate hepatic stellate cells, the fibrogenic cell in the liver, and drive liver scarring. The release of mito-DAMPs is controlled by efferocytosis of dying hepatocytes by phagocytic resident liver macrophages and infiltrating Gr-1(+) myeloid cells. Circulating mito-DAMPs are markedly increased in human patients with non-alcoholic steatohepatitis (NASH) and significant liver fibrosis. Our study identifies specific pathway driving liver fibrosis, with important diagnostic and therapeutic implications. Targeting mito-DAMP release from hepatocytes and/or modulating the phagocytic function of macrophages represents a promising antifibrotic strategy.