Innate immune signaling relays environmental cues to mitophagy for metabolic adaptation to obesity.

The mechanisms by which pancreatic β cells sense and communicate environmental cues to mitochondria to maintain insulin secretion remain poorly understood. We identified that β cells transduce metabolic stress, such as during obesity or glucolipotoxicity, through the innate immune signaling adaptor TRAF6 to regulate mitochondrial quality control. TRAF6 was dispensable for β-cell function at baseline yet was essential for glucose-stimulated insulin secretion in mouse or human β cells following nutrient excess. TRAF6 was required for the recruitment of components of both ubiquitin- and receptor-mediated mitophagy pathways to clear dysfunctional mitochondria following metabolic stress. Interestingly, concomitant loss of the ubiquitin-mediated mitophagy effector Parkin restored glucose homeostasis and mitophagy flux in TRAF6-deficient β cells by relieving impediments in receptor-mediated mitophagy. Together, we found that TRAF6 forms a molecular relay linking environmental signals to multiple mitophagy pathways to equip β cells with the means to adapt to metabolic demand and prevent diabetes.Abbreviations: ADP: adenosine diphosphate; ATP: adenosine triphosphate; BNIP3: BCL2 interacting protein 3; GSIS: glucose-stimulated insulin secretion; HFD: high-fat diet; MFN2: mitofusin 2; PRKN: parkin RBR E3 ubiquitin protein ligase; RNF41/NRDP1: ring finger protein 41; SQSTM1/p62: sequestosome 1; T2D: type 2 diabetes; TAX1BP1: Tax1 binding protein 1; TLR: Toll-like receptor; TRAF6: TNF receptor associated factor 6.