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.