IFI27 Integrates Succinate and Fatty Acid Oxidation to Promote Adipocyte Thermogenic Adaption

Mitochondria are the pivot organelles to control metabolism and energy homeostasis. The capacity of mitochondrial metabolic adaptions to cold stress is essential for adipocyte thermogenesis. How brown adipocytes keep mitochondrial fitness upon a challenge of cold-induced oxidative stress has not been well characterized. This manuscript shows that IFI27 plays an important role in cristae morphogenesis, keeping intact succinate dehydrogenase (SDH) function and active fatty acid oxidation to sustain thermogenesis in brown adipocytes. IFI27 protein interaction map identifies SDHB and HADHA as its binding partners. IFI27 physically links SDHB to chaperone TNF receptor associated protein 1 (TRAP1), which shields SDHB from oxidative damage-triggered degradation. Moreover, IFI27 increases hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA) catalytic activity in & beta;-oxidation pathway. The reduced SDH level and fatty acid oxidation in Ifi27-knockout brown fat results in impaired oxygen consumption and defective thermogenesis. Thus, IFI27 is a novel regulator of mitochondrial metabolism and thermogenesis.

Automated summary

This study reveals the important role of IFI27 in maintaining mitochondrial morphology and function in brown adipocytes. IFI27 interacts with SDHB and HADHA proteins, and protects SDHB from oxidative damage-induced degradation by linking it to TRAP1. Additionally, IFI27 enhances the catalytic activity of HADHA in the β-oxidation pathway. Loss of IFI27 leads to reduced SDH levels and impaired fatty acid oxidation, resulting in defective oxygen consumption and thermogenesis in brown fat. Overall, IFI27 is a novel regulator of mitochondrial metabolism and thermogenesis.