Excessive EFHD1-dependent ER-mitochondrial contacts drive a maladaptive antiviral response in metabolic liver disease.

ABSTRACT: Metabolic dysfunction-associated steatohepatitis (MASH) involves hepatocyte damage that cannot be explained solely by lipid accumulation. Here, to discover injury-specific pathways, we focused on a gene of uncertain function, EF-hand domain family member D1 (EFHD1), identified in human genome-wide association studies of liver injury but not liver fat. We showed that EFHD1, a Ca2+-dependent actin cross-linker, stabilizes endoplasmic reticulum-mitochondria contact sites (ERMCS) by detecting spatiotemporal coincidence of interorganellar proximity and ER Ca2+ release. During MASH, EFHD1 upregulation drives pathological mitochondrial fragmentation via excessive contact persistence. This structural failure promotes mitochondrial double-stranded RNA escape and activation of a maladaptive, antivir

SUBMITTER: Eberhardt DR 

PROVIDER: S-EPMC13626817 | biostudies-literature | 2026 Oct

REPOSITORIES: biostudies-literature