Metabolic-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 show that EFHD1, a Ca2+-dependent actin crosslinker, stabilizes endoplasmic reticulum-mitochondria contact sites (ERMCS), detecting spatiotemporal coincidence of inter-organellar 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 PKR-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.
D. Eberhardt, Emma C. Rekate, Yasmin B. Masini et al.· Journal of Clinical Investig...· 0 citations
Inner mitochondrial membrane proteins must be sufficiently hydrophilic to withstand aqueous exposure during translation and transit to the mitochondria. Meanwhile, their transmembrane segments must be sufficiently hydrophobic to stably embed in the lipid membrane. We hypothesized that sequence-level adaptations evolved to balance these constraints. Here, we integrate structure-informed evolutionary analyses of mitochondrial proteins with atomistic simulations and cell-based experiments to identify aliphatic-to-threonine substitutions (ATS) as a potential solution to these constraints. With high statistical confidence, this transmembrane segment-specific adaptation is recurrently and convergently observed throughout mitochondrial evolution. Conformational analyses show that threonine interacts with both water and the transmembrane helix backbone, thereby lowering hydrophobicity without destabilizing secondary structure. In the extremely hydrophobic ATP6 protein, reverting threonines to aliphatic residues disrupts mitochondrial targeting, while introducing threonines into a poorly targeted variant improves its mitochondrial localization. These findings have implications for mitochondrial genome evolution, the rational design of membrane proteins, and potentially mitochondrial gene therapy.
Tarun Yadav, Jonathan Borowsky, Á. Narbona-Pérez et al.· bioRxiv· 0 citations
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