CLPP loss confers sex-specific protection from renal ischemia reperfusion injury

Renal ischemia-reperfusion injury (IRI) is initiated by a burst of mitochondrial reactive oxygen species generated when ischemia-accumulated succinate is rapidly oxidised upon reperfusion, driving reverse electron transport and triggering lipid peroxidation-dependent tubular cell death. Here, we identify the mitochondrial matrix protease CLPP as an unexpected regulator of renal redox resilience. CLPP deficiency reduced succinate-driven mitochondrial H₂O₂ production and protected kidneys from functional decline, tubular necrosis, mitochondrial ultrastructural damage, and lipid peroxidation following IRI. Protection was most pronounced in females, in which CLPP loss established a constitutive antioxidant and detoxification programme prior to injury, characterised by increased glutathione and γ-glutamylcysteine abundance, enhanced NADPH-generating pentose phosphate pathway activity, sustained sulphur amino acid metabolism, and elevated capacity for lipid aldehyde detoxification. During reperfusion, these adaptations preserved thiol-redox buffering, limited 4-hydroxynonenal accumulation, and reduced oxidative modification of cysteine residues on proteins involved in complement, coagulation, fibrinolysis, and inflammatory signalling, thereby restricting ferroptotic lipid damage and downstream thrombo-inflammatory amplification. Although reduced reverse electron transport-derived ROS contributed to this phenotype, it was insufficient to account for the sex bias. While CLPP deficiency amplified an endogenous female antioxidant programme, male kidneys, lacking equivalent glutathione-centred preconditioning, showed only marginal benefit. These findings establish mitochondrial proteostasis as a determinant of sex-dependent redox adaptation and identify CLPP as a candidate target for preconditioning against predictable ischaemic insults, including kidney transplantation and cardiac surgery.