IF1 connects obesity and insulin resistance through mitochondrial reprogramming in association with ANT2

Wang, Y.; Guan, Y.; Zhang, J.; Cao, X.; Shen, S.; Zhong, G.; Xong, X.; Xu, Y.; Zhang, X.; Wang, H.; Ye, J.

doi:10.1101/2020.09.24.311076

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bioRxiv · 10.1101/2020.09.24.311076

IF1 connects obesity and insulin resistance through mitochondrial reprogramming in association with ANT2

Wang, Y.·Guan, Y.·Zhang, J.·Cao, X.·Shen, S.·Zhong, G.·Xong, X.·Xu, Y.·Zhang, X.·Wang, H.·Ye, J.

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Abstract

IF1 (ATPIF1) is a nuclear DNA-encoded protein with an activity in the inhibition of catalytic activity of F1Fo-ATP synthase (ATPase), an enzyme for ATP synthesis in mitochondria. A role of IF1 remains unknown in the metabolic disorder in obesity. In this study, IF1 was examined in the diet-induced obese (DIO) mice and a decrease in IF1 protein was observed in several tissues including the skeletal muscle, liver and intestine in the absence of mRNA alteration. Significance of the reduction was investigated in the IF1-KO mice, in which insulin sensitivity was improved in the absence of body weight alteration on Chow diet. On a high fat diet (HFD), the IF1-KO mice gain more body weight as a result of enhanced fat tissue growth. The energy expenditure and locomotion activity were decreased in the KO mice without an alteration in food intake. The increase in insulin sensitivity remained in the obese KO mice. The colon tissue exhibited a resistance to the HFD-induced atrophy with less cell apoptosis and more secretion of GLP-1. Mitochondria exhibited an enhanced ATP production and maximal oxygen consumption without an alteration in the respiratory chain proteins. However, the ATP level was reduced in the fasting condition in the muscle as well as the liver. Mitophagy was enhanced with elevated accumulation of PINK1 and Parkin proteins in the mitochondria. The protein abundance of ADP/ATP translocase 2 (ANT2) was decreased in the inner membrane of mitochondria to account for the reduced apoptosis and enhanced mitophagy. The data suggest that the IF1 reduction in obesity leads to reprogramming of mitochondrial metabolism in a compensatory response to maintain the insulin sensitivity through down-regulation of ANT2 protein.

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Wang, Y., Guan, Y., Zhang, J., Cao, X., Shen, S., Zhong, G., Xong, X., Xu, Y., Zhang, X., Wang, H., Ye, J.. 2020-09-25. IF1 connects obesity and insulin resistance through mitochondrial reprogramming in association with ANT2. https://doi.org/10.1101/2020.09.24.311076

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