Isocitrate dehydrogenase 2 (IDH2) is an NADP+-dependent enzyme that catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate in the mitochondrial matrix, and is critical for the production of NADPH to limit the accumulation of mitochondrial reactive oxygen species (ROS). Here, we showed that high-fat diet (HFD) feeding resulted in accelerated weight gain in the IDH2KO mice due to a reduction in whole-body energy expenditure. Moreover, the levels of NADP+, NADPH, NAD+, and NADH were significantly decreased in the brown adipose tissue (BAT) of the HFD-fed IDH2KO animals, accompanied by decreased mitochondrial function and reduced expression of key genes involved in mitochondrial biogenesis, energy expenditure, and ROS resolution. Interestingly, these changes were partially reversed when the antioxidant butylated hydroxyanisole was added to the HFD. These observations reveal a crucial role for IDH2 in limiting ROS-dependent mitochondrial damage when BAT metabolism is normally enhanced to limit weight gain in response to dietary caloric overload.
Bibliographical noteFunding Information:
This study was supported by grants from the Korea Research Foundation, an NRF grant funded by the Korea Government (MSIP) (2016R1A2B4008516 and 2019R1H1A2079849), the Medical Research Center (2014R1A5A2010008), and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HR18C0012) to S.S.I., an NIH grant (RO1HL48044) to T.F.O., GRL 2017K1A1A2013124 to M.S. and a grant of Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Minstry of Health and Welfare, the Republic of Korea (HI16C1501) to I.K.L. We thank Dan Kelly for comments on the paper and Lorenzo Thomas for help with the paper organization and submission.
© 2020, The Author(s).
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Clinical Biochemistry