PGAM5 modulates PI3K/AKT/mTOR-dependent mitochondrial homeostasis in sepsis-induced acute kidney injury

Sepsis-induced acute kidney injury (S-AKI) is a frequent and life-threatening complication in critically ill patients and is largely driven by mitochondrial metabolic dysfunction in renal tubular epithelial cells, yet the upstream regulatory mechanisms remain incompletely understood. In this study, we investigated the role of phosphoglycerate mutase family member 5 (PGAM5) in S-AKI using lipopolysaccharide (LPS)-treated renal tubular epithelial cells and murine models of sepsis. PGAM5 expression was markedly upregulated under septic conditions. Functional gain- and loss-of-function analyses demonstrated that PGAM5 exacerbated tubular cell injury and mitochondrial dysfunction, whereas PGAM5 knockdown preserved mitochondrial homeostasis, as evidenced by improved cell viability, reduced LDH release and pro-inflammatory cytokine production, decreased apoptosis, restored mitochondrial membrane potential, increased ATP generation, and reduced ROS and MDA levels. Mechanistically, PGAM5 dysregulation was associated with modulation of the PI3K/AKT/mTOR signaling pathway, and pharmacological inhibition of PI3K abolished the protective effects conferred by PGAM5 depletion, indicating pathway involvement. Consistently, in vivo PGAM5 knockdown alleviated sepsis-induced renal dysfunction, histopathological injury, and mitochondrial impairment, accompanied by restoration of PI3K/AKT/mTOR activity. Together, these findings suggest that PGAM5 contributes to S-AKI, at least in part via modulation of PI3K/AKT/mTOR-dependent mitochondrial metabolic homeostasis, while the precise molecular interactions underlying this regulation remain to be elucidated.