Objectives: Mitochondria are highly dynamic organelles that continuously undergo biogenesis, fusion, fission, and mitophagy to regulate cellular energy metabolism, calcium homeostasis, and the synthesis of hormones, sterols, and bile acids (BAs). In this study, we investigated how impaired mitochondrial fusion in hepatocytes affects diet-induced hepatic steatosis and obesity.
Methods and Results: Male mice selectively lacking the key inner mitochondrial fusion protein optic atrophy 1 (OPA1) (OPA1ΔHep) were fed a high-fat diet (HFD) for 20 weeks. OPA1ΔHep mice were protected from developing hepatic steatosis and obesity due to reduced lipid absorption — a phenotype accompanied by an increased respiratory exchange ratio in vivo, indicating a preferential utilization of carbohydrates in OPA1ΔHep mice compared with controls.
At the molecular level, this phenotype resulted from defective mitochondria–peroxisome–endoplasmic reticulum (ER) tethering in OPA1-deficient hepatocytes, which impaired bile acid conjugation and secretion, thereby limiting lipid absorption from the diet. Consistently, livers from subjects with non-alcoholic fatty liver disease (NAFLD) exhibited increased expression of OPA1 and the associated mitochondrial functional protein network compared with controls.
Conclusion: Patients with NAFLD display elevated hepatic expression of proteins involved in mitochondrial fusion. Selective loss of OPA1 in hepatocytes protects mice from high-fat-diet-induced metabolic dysfunction by reducing bile acid secretion and dietary lipid absorption, due to impaired mitochondria–peroxisome–ER tethering in the liver.
Support Our Research
Support Our Research
