Role of mitochondria-associated ER membranes in lipid metabolism: implications for renal lipotoxicity

Abstract

Abstract Dysregulated lipid metabolism is implicated in renal injury associated with diabetic nephropathy, acute kidney injury, chronic kidney disease, nephrotic syndrome, and renal cell carcinoma. However, its causal role and mechanisms remain ambiguous. Mitochondria-associated ER membranes (MAMs) are contact sites between the endoplasmic reticulum and mitochondria that facilitate the integration of lipid trafficking, mitochondrial metabolism, calcium signaling, and redox homeostasis within cells. Recent evidence from patient biopsies and experimental renal models suggests that altered MAM integrity is linked to ectopic lipid deposition, mitochondrial dysfunction, oxidative stress, and renal injury. The present review examines evidence suggesting that MAM dysregulation may contribute to the abnormal metabolism of phospholipids (PLs), ceramides, cholesterol, fatty acids, and triglycerides in renal cells, thereby addressing a gap between previous reviews on renal lipotoxicity and those focusing on MAM-dependent calcium signaling in kidney diseases. Key mechanisms include impaired PL transfer with disrupted cardiolipin remodeling, ceramide-associated mitochondrial injury, defective fatty acid oxidation, and acyl-CoA synthetase long-chain family member 4-mediated PL peroxidation, leading to renal ferroptosis. Direct evidence for MAM-regulated lipid droplet degradation in the kidney is limited; thus, findings from non-renal cells are differentiated from kidney-specific observations. MAM-associated proteins have emerged as potential therapeutic targets in preclinical studies. However, renoprotective effects of sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists related to MAMs remain indirect and necessitate validation. Restoring the structural and functional integrity of MAMs could represent a promising strategy to mitigate lipid-induced renal injury.