Excessive Ca2+-dependent ER-mitochondrial contact stabilization by EFHD1 drives liver injury

Eberhardt, D. R.; Rekate, E. C.; Masini, Y. B.; Duron, H. E.; Mollinedo, D.; Velarde, A. M.; Stucki, D.; Price, T.; Lee, S. H.; Balderas, E.; Rai, N. K.; Bratt, A. R.; Balynas, A. M.; Stubben, C. J.; Bia, R.; Maity, S.; Hartel, N.; Yin, X.; Corbin, A.; Kumari, A.; Nguyen, D. M.; Shimura, D.; Nguyen, V. D.; Vinod, V.; Chowdhury, K. H.; Verdeguer, F.; Zvick, J.; Mimche, P. N.; Boudina, S.; Drakos, S. G.; Aromolaran, A. S.; Franklin, S.; Garg, V.; Shaw, R. M.; Holland, W. L.; Summers, S. A.; Pezzolesi, M. G.; Rutter, J.; Evason, K. J.; Chaudhuri, D.

doi:10.64898/2026.02.13.705622

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bioRxiv · 10.64898/2026.02.13.705622

Excessive Ca2+-dependent ER-mitochondrial contact stabilization by EFHD1 drives liver injury

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Abstract

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-dependent 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.

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Eberhardt, D. R., Rekate, E. C., Masini, Y. B., Duron, H. E., Mollinedo, D., Velarde, A. M., Stucki, D., Price, T., Lee, S. H., Balderas, E., Rai, N. K., Bratt, A. R., Balynas, A. M., Stubben, C. J., Bia, R., Maity, S., Hartel, N., Yin, X., Corbin, A., Kumari, A., Nguyen, D. M., Shimura, D., Nguyen, V. D., Vinod, V., Chowdhury, K. H., Verdeguer, F., Zvick, J., Mimche, P. N., Boudina, S., Drakos, S. G., Aromolaran, A. S., Franklin, S., Garg, V., Shaw, R. M., Holland, W. L., Summers, S. A., Pezzolesi, M. G., Rutter, J., Evason, K. J., Chaudhuri, D.. 2026-02-16. Excessive Ca2+-dependent ER-mitochondrial contact stabilization by EFHD1 drives liver injury. https://doi.org/10.64898/2026.02.13.705622

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