Hepatic Suppression of Mitochondrial Complex II Assembly Drives Systemic Metabolic Benefits

• Published in: Advanced science 2022-03, Vol.9 (9), p.e2105587-n/a
• Main Authors: Wang, Xueqiang, Lv, Weiqiang, Xu, Jie, Zheng, Adi, Zeng, Mengqi, Cao, Ke, Wang, Xun, Cui, Yuting, Li, Hao, Yang, Meng, Shao, Yongping, Zhang, Fang, Zou, Xuan, Long, Jiangang, Feng, Zhihui, Liu, Jiankang
• Format: Article
• Language: English
• Subjects: Animals; Body fat; Caloric Restriction; complex II; Creatinine; Diabetes; dietary restriction; Fasting; Genotype & phenotype; Glucose; Hepatocytes; Humans; Insulin; Insulin Resistance - physiology; insulin sensitivity; Liver; Metabolism; Metabolites; Mice; Mitochondria; Musculoskeletal system; Physiology; Proteins; Rodents; SDHAF4; Weight control
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202105587

Alternate day fasting (ADF), the most popular form of caloric restriction, has shown to improve metabolic health in preclinical subjects, while intrinsic network underpinning the process remains unclear. Here, it is found that liver undergoes dramatic metabolic reprogramming during ADF, accompanied surprisingly with unique complex II dysfunction attributing to suspended complex II assembly via suppressing SDHAF4, a recently identified assembly factor. Despite moderate mitochondrial complex II dysfunction, hepatic Sdhaf4 knockout mice present intriguingly improved glucose tolerance and systemic insulin sensitivity, consistent with mice after ADF intervention. Mechanistically, it is found that hepatocytes activate arginine‐nitric oxide (NO) biosynthesis axle in response to complex II and citric acid cycle dysfunction, the release of NO from liver can target muscle and adipocytes in addition to its autocrine action for enhanced insulin sensitivity. These results highlight the pivotal role of liver in ADF‐associated systemic benefits, and suggest that targeting hepatic complex II assembly can be an intriguing strategy against metabolic disorders. Alternate day fasting (ADF) decreases complex II activity in liver via suppressing its assembly. Such suppression drives compensatory activation of arginine metabolism, resulting in hepatic release of nitric oxide for promoting systemic insulin sensitivity. The study sets an unique example supporting diverse effects of mitochondrial function in maintaining health, and raising interests in further exploration of intricate mitochondrial metabolic network.