Mitochondrial dysfunction in sepsis-associated acute kidney injury: mechanisms and therapeutic potential

Sepsis-associated acute kidney injury (SA-AKI) is a life-threatening complication in critically ill adult patients, accounting for nearly 50% of acute kidney injury (AKI) cases in intensive care units and carrying a mortality rate exceeding 40%. Its pathogenesis extends beyond traditional concepts of renal hypoperfusion to encompass a complex interplay of systemic inflammation, microcirculatory dysfunction, and profound metabolic reprogramming. Converging evidence now positions mitochondrial dysfunction as a central hub that integrates these pathogenic insults, ultimately driving tubular epithelial cell injury and renal functional decline. Importantly, mitochondrial dysfunction interfaces with innate immune activation (e.g., the mtDNA-cGAS-STING pathway) and immunometabolic reprogramming in both renal parenchymal and immune cells. This highlights mitochondria-immune crosstalk as a key determinant of SA-AKI pathogenesis. This review systematically examines the multidimensional nature of mitochondrial impairment in SA-AKI, including bioenergetic failure, disrupted fusion-fission dynamics, compromised quality control mechanisms, and aberrant redox signaling. We further explore the therapeutic potential of targeting mitochondrial pathways, critically assessing emerging strategies and their translational challenges, and discuss future directions for developing mechanism-based diagnostics and targeted therapies for this devastating syndrome.