Superoxide dismutase (SOD) catalyzes the dismutation of superoxide radical (O2•-) to hydrogen peroxide (H2O2). There are three human SOD isoforms with different metal cofactors. Which isoform is located in the mitochondrial matrix and is the primary defense against mitochondrial superoxide generated by electron leakage?

• A SOD1 (Cu/Zn-SOD) in the cytoplasm and mitochondrial intermembrane space
• B SOD3 (Cu/Zn-SOD) extracellular/secreted isoform in plasma and extracellular matrix
• C SOD2 (Mn-SOD) in the mitochondrial matrix ✓
• D Catalase in peroxisomes converting superoxide directly to water

Explanation

SOD2 (Mn-SOD, encoded by the SOD2 gene on nuclear DNA) contains manganese as its metal cofactor and is specifically localized to the mitochondrial matrix. It is the primary scavenger of superoxide radicals generated by electron leakage at Complexes I and III of the ETC. SOD2 knockout mice develop dilated cardiomyopathy and die within days, underscoring its critical role. SOD2 mutations are associated with various cancers, as oxidative stress promotes mutagenesis. SOD1 (Cu/Zn) operates in the cytoplasm and mitochondrial IMS; mutations in SOD1 cause familial ALS.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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