SIRT3 regulates PRDX3 acetylation to support mitochondrial peroxide detoxification and limit oxidative...

Oxidative stress disrupts mitochondrial redox homeostasis and contributes to ferroptosis-associated vulnerability, yet the molecular link between impaired mitochondrial peroxide detoxification and ferroptosis-associated vulnerability remains incompletely defined. Here, we identify PRDX3 as a candidate SIRT3-regulated effector of mitochondrial peroxide control. In AML12 cells, oxidative stress reduced mitochondrial SENP1, increased SIRT3 SUMOylation and elevated mitochondrial protein acetylation. Mitochondrial acetylome profiling identified PRDX3 K92 as a SIRT3-responsive acetylation site. Genetic activation of SIRT3 reduced PRDX3 acetylation and was associated with enhanced PRDX3 dimerization, improved peroxide clearance and reduced mitochondrial H₂O₂, lipid peroxidation, iron accumulation and other ferroptosis-associated changes. Conversely, an acetylation-mimetic PRDX3 mutant impaired peroxide clearance and attenuated the protective phenotype associated with SIRT3 activation, whereas a deacetylation-mimetic mutant improved redox balance and cell viability under oxidative stress. In vivo, activation of the SIRT3-PRDX3 axis mitigated paraquat-induced liver injury. Collectively, these data support a model in which SIRT3-dependent regulation of PRDX3 acetylation helps sustain mitochondrial peroxide detoxification and limits oxidative injury during stress.