A Novel and Evolutionarily Conserved Metabolic Axis for Efficient Hepatic Lipid Catabolism Governed by Mfn2-Hsl-Mediated Mitochondria-Lipid Droplet Coupling
- 1Huazhong Agricultural University
Abstract
Inter-organelle contact between mitochondria and lipid droplets (LDs) is crucial for hepatic lipid homeostasis, but the tethering complex underlying this interaction remains unclear. To address this, we aimed to characterize the molecular machinery governing mitochondria-LD coupling and evaluate the evolutionary conservation of its metabolic functions. Using hepatocyte models from multiple species and in vivo experiments in yellow catfish with differential lipid and creatine diets, we explored the mechanism and evolutionary conservation of mitochondria-LD coupling. The key findings were: (1) A novel complex formed by mitofusin 2 on mitochondria and hormone-sensitive lipase on lipid droplets via specific residues orchestrates efficient hepatic lipid catabolism by mediating mitochondria-LD coupling; (2) Creatine enhances this coupling by transcriptionally upregulating mfn2 via hnf4, thereby promoting peridroplet mitochondria formation and alleviating hepatic lipid accumulation; (3) The Mfn2-phosphorylated HSL axis is evolutionarily conserved across fish and mammals, representing a potential therapeutic target for hepatic steatosis.
Related
- Evidence for a regulatory role of the evolutionarily conserved sequence complementarity between tRNAs
- The evolutionarily conserved C-terminal domain of a domesticated transposase-derived protein regulates its DNA integration ability
- An Evolutionarily Conserved Ypk1/SGK1 Kinase Pathway Regulates the Unfolded Protein Response by Modulating the Ire1 Protein Abundance
- An evolutionarily conserved interferon-responsive oligodendroglial state emerges during white matter aging
- Natural variation in the evolutionarily conserved F-box gene SDEF promotes seed dormancy in rice.
BibTeX
@misc{chi2026novel,
title = {{A Novel and Evolutionarily Conserved Metabolic Axis for Efficient Hepatic Lipid Catabolism Governed by Mfn2-Hsl-Mediated Mitochondria-Lipid Droplet Coupling}},
author = {Y.-J. Chi and Z.-X. Liu and N.-J. Hu and G.-L. Feng and Y. Song},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.28.754920},
url = {https://www.biorxiv.org/content/10.64898/2026.09.28.754920v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - A Novel and Evolutionarily Conserved Metabolic Axis for Efficient Hepatic Lipid Catabolism Governed by Mfn2-Hsl-Mediated Mitochondria-Lipid Droplet Coupling
AU - Y.-J. Chi
AU - Z.-X. Liu
AU - N.-J. Hu
AU - G.-L. Feng
AU - Y. Song
PY - 2026
DA - 2026/09/28
PB - bioRxiv
DO - 10.64898/2026.09.28.754920
UR - https://www.biorxiv.org/content/10.64898/2026.09.28.754920v1
AB - Inter-organelle contact between mitochondria and lipid droplets (LDs) is crucial for hepatic lipid homeostasis, but the tethering complex underlying this interaction remains unclear. To address this, we aimed to characterize the molecular machinery governing mitochondria-LD coupling and evaluate the evolutionary conservation of its metabolic functions. Using hepatocyte models from multiple species and in vivo experiments in yellow catfish with differential lipid and creatine diets, we explored the mechanism and evolutionary conservation of mitochondria-LD coupling. The key findings were: (1) A novel complex formed by mitofusin 2 on mitochondria and hormone-sensitive lipase on lipid droplets via specific residues orchestrates efficient hepatic lipid catabolism by mediating mitochondria-LD coupling; (2) Creatine enhances this coupling by transcriptionally upregulating mfn2 via hnf4, thereby promoting peridroplet mitochondria formation and alleviating hepatic lipid accumulation; (3) The Mfn2-phosphorylated HSL axis is evolutionarily conserved across fish and mammals, representing a potential therapeutic target for hepatic steatosis.
ER -