Excessive EFHD1-dependent ER-mitochondrial contacts drive a maladaptive antiviral response in metabolic liver disease
TL;DR
It is shown 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, and suggested EFHD1 inhibition as a therapeutic strategy.
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, antiviral, protein kinase RNA-activated–associated stress response, a causal relationship also supported by Mendelian randomization in humans. Consequently, inhibiting EFHD1 in human and mouse models blunts hepatocyte damage. These findings identify EFHD1 as a Ca2+-dependent ERMCS stabilizer, reveal a hepatocyte-intrinsic injury pathway, and suggest EFHD1 inhibition as a therapeutic strategy.