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EFHD1 promotes hepatocyte injury in metabolic liver disease by triggering Ca2+-dependent mitochondrial fission

ABSTRACT: Human genome-wide association studies (GWAS) of metabolic-associated steatohepatitis (MASH), the most common liver disease worldwide, have examined either liver injury biomarkers or liver fat content, with lipid metabolism enzymes ranked highly in both analyses. Here, to define pathophysiological pathways independent of lipid metabolism, we focused on a gene of unknown function found in liver biomarker but not liver fat GWAS, EF-Hand Domain Family Member D1 (EFHD1). We now identify EFHD1 as the factor transducing endoplasmic reticulum calcium (Ca2+) release into a mitochondrial fission signal. Mechanistically, EFHD1 ablation prevented Ca2+-dependent actin rearrangements that support fission. Moreover, EFHD1 was critical for increased hepatocyte mitochondrial fission noted during MASH, and promoted cytoplasmic release of mitochondrial double-stranded RNA, a damage-associated molecular pattern driving an integrated stress response and injury via the protein kinase PKR. Finally, acutely inhibiting EFHD1 in mice developing MASH did not substantially alter steatosis but blunted hepatocyte injury, inflammation, and fibrosis.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Hepatocyte, Liver

DISEASE(S): Non-alcoholic Steatohepatitis

SUBMITTER: Ryan Bia

LAB HEAD: Sarah Franklin

PROVIDER: PXD069152 | Pride | 2026-07-30

REPOSITORIES: Pride

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			Action	DRS
	ProteinPeptide_UtahMouseLiver_500ng_4groups_LFQ_IO25_Report.csv	Csv
	Utah_MouseLiver_10_KOCHOW_413_25minDIA_2pt5uL_Rep1.raw	Raw
	Utah_MouseLiver_10_KOCHOW_413_25minDIA_2pt5uL_Rep2.raw	Raw
	Utah_MouseLiver_10_KOCHOW_413_25minDIA_2pt5uL_Rep3.raw	Raw
	Utah_MouseLiver_11_WTGAN_3823_25minDIA_2pt5uL_Rep1.raw	Raw

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