The pro-inflammatory cytokine IL6 suppresses mitochondrial function via the gp130-JAK1/STAT1/3-HIF1α/ERRα axis
Jianing Xu, Matthew Wakai, Kun Xiong, Yanfeng Yang, Adithya Prabakaran, Sophia P. Wu, Diana Ahrens, Maria del Pilar Molina‐Portela, Min Ni, Yu Bai, Tea Shavlakadze, David J. Glass
Abstract
Chronic inflammation and a decline in mitochondrial function are hallmarks of aging. Here, we show that the two mechanisms may be linked. We found that interleukin-6 (IL6) suppresses mitochondrial function in settings where PGC1 (both PGC1α and PGC1β) expression is low. This suppression is mediated by the JAK1/STAT1/3 axis, which activates HIF1α through non-canonical mechanisms involving upregulation of HIF1A and ERRα transcription, and subsequent stabilization of the HIF1A protein by ERRα. HIF1α, in turn, inhibits ERRα, which is a master regulator of mitochondrial biogenesis, thus contributing to the inhibition of mitochondrial function. When expressed at higher levels, PGC1 rescues ERRα to boost baseline mitochondrial respiration, including under IL6-treated conditions. Our study suggests that inhibition of the IL6 signaling axis could be a potential treatment for those inflammatory settings where mitochondrial function is compromised.