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, influences resistance to high-fat-diet-induced obesity in AKO but not BKO mice. This resistance is mediated by an increase in mitochondrial cristae that stabilizes oxidative phosphorylation (OXPHOS) complexes and enhances energy expenditure. Our protein-interactome analysis reveals that GCN5L1 is associated with the mitochondrial crista complex MICOS (MIC13) and the protease YME1L, facilitating the degradation of MICOS and disassembly of cristae during obesity. This interaction results in decreased OXPHOS levels and subsequent adipocyte expansion. Accumulation of GCN5L1 in the mitochondrial intermembrane space is triggered by a high-fat diet. Our findings highlight a regulatory pathway involving YME1L/GCN5L1/MIC13 that remodels mitochondrial cristae in WAT in response to overnutrition-induced obesity.