Mitochondrial GCN5L1 coordinates with YME1L and MICOS to remodel mitochondrial cristae in white adipocytes and modulate obesity

The relationship between mitochondrial architecture and energy homeostasis in adipose tissues is not well understood. In this study, we utilized GCN5L1 knockout mice in white (AKO) and brown (BKO) adipose tissues to examine mitochondrial homeostasis in adipose tissues. GCN5L1, a regulator of mitochondrial metabolism and dynamics, influenced resistance to high-fat diet-induced obesity in AKO but not BKO mice. This resistance was mediated by an increase in mitochondrial cristae that stabilized OXPHOS complexes and enhanced energy expenditure. Our protein-interactome analysis revealed that GCN5L1 is associated with the mitochondrial cristae complex MICOS (specifically MIC13) and the protease YME1L, facilitating the degradation of MICOS and disassembly of cristae during obesity. This interaction resulted in decreased OXPHOS levels and subsequent adipocyte expansion. Notably, GCN5L1 mitochondrial intermembrane space accumulation was triggered by a high-fat diet. Our findings highlight a novel regulatory pathway involving YME1L/GCN5L1/MIC13 that remodels mitochondrial cristae in WAT in response to overnutrition-induced obesity.