The pro-inflammatory cytokine IL6 suppresses mitochondrial function via the gp130-JAK1/STAT1/3-HIF1α/ERRα axis

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.