OPA1 controls mitochondrial dysfunction-driven liver fibrosis in MASLD
- 1Beth Israel Deaconess Medical Center, Harvard Medical School
Abstract
Progressive hepatic fibrosis is the principal determinant of morbidity and mortality in metabolic dysfunction-associated steatotic liver disease and steatohepatitis (MASLD/MASH). Mitochondrial dysfunction is a hallmark of MASH, and the release of mitochondrial damage-associated molecular patterns (mito-DAMPs) from injured hepatocytes can promote fibrosis. However, how mitochondrial dynamics and quality control shape the fibrotic response in MASLD/MASH remains unclear. Here, through large-scale genomic analyses of mitochondrial genes governing mitophagy, fusion and fission in human MASLD, with a power-equivalent sample size of approximately 700,000 individuals, we identify a strong association between hepatic fibrosis and the mitochondrial fusion factor dynamin-like GTPase optic atrophy 1 (OPA1). OPA1 transcripts and protein abundance in the liver epithelium were progressively dysregulated with advancing fibrosis. In mice, hepatocyte-specific OPA1 loss alone was sufficient to induce hepatic stellate cell activation and fibrosis in zone 3, promoted the release of mito-DAMPs into the circulation and exacerbated fibrosis in experimental MASH. These findings identify OPA1 as a central regulator of the hepatic fibrotic response and connect defective mitochondrial homeostasis to mito-DAMP release, hepatic stellate cell activation and fibrosis in MASLD.
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BibTeX
@misc{yu2026opa1,
title = {{OPA1 controls mitochondrial dysfunction-driven liver fibrosis in MASLD}},
author = {X. Yu and P. Huang and A. Justice and A. Hakim and Y. Nanki and Z. Abilov and E. B. O'Neill and J. Cruz Rodriguez and E. Cabrera and M. Sagatelian and C. S. Shankar and B. R. Flam and K. Al Khalloufi and H. Sesaki and S. Rong and Y. V. Popov},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.24.753666},
url = {https://www.biorxiv.org/content/10.64898/2026.09.24.753666v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - OPA1 controls mitochondrial dysfunction-driven liver fibrosis in MASLD
AU - X. Yu
AU - P. Huang
AU - A. Justice
AU - A. Hakim
AU - Y. Nanki
AU - Z. Abilov
AU - E. B. O'Neill
AU - J. Cruz Rodriguez
AU - E. Cabrera
AU - M. Sagatelian
AU - C. S. Shankar
AU - B. R. Flam
AU - K. Al Khalloufi
AU - H. Sesaki
AU - S. Rong
AU - Y. V. Popov
PY - 2026
DA - 2026/09/24
PB - bioRxiv
DO - 10.64898/2026.09.24.753666
UR - https://www.biorxiv.org/content/10.64898/2026.09.24.753666v1
AB - Progressive hepatic fibrosis is the principal determinant of morbidity and mortality in metabolic dysfunction-associated steatotic liver disease and steatohepatitis (MASLD/MASH). Mitochondrial dysfunction is a hallmark of MASH, and the release of mitochondrial damage-associated molecular patterns (mito-DAMPs) from injured hepatocytes can promote fibrosis. However, how mitochondrial dynamics and quality control shape the fibrotic response in MASLD/MASH remains unclear. Here, through large-scale genomic analyses of mitochondrial genes governing mitophagy, fusion and fission in human MASLD, with a power-equivalent sample size of approximately 700,000 individuals, we identify a strong association between hepatic fibrosis and the mitochondrial fusion factor dynamin-like GTPase optic atrophy 1 (OPA1). OPA1 transcripts and protein abundance in the liver epithelium were progressively dysregulated with advancing fibrosis. In mice, hepatocyte-specific OPA1 loss alone was sufficient to induce hepatic stellate cell activation and fibrosis in zone 3, promoted the release of mito-DAMPs into the circulation and exacerbated fibrosis in experimental MASH. These findings identify OPA1 as a central regulator of the hepatic fibrotic response and connect defective mitochondrial homeostasis to mito-DAMP release, hepatic stellate cell activation and fibrosis in MASLD.
ER -