TXNRD2

TXNRD2, or thioredoxin reductase 2, is a mitochondrial selenoprotein that belongs to the thioredoxin reductase enzyme family. The gene encoding TXNRD2 is nuclear, and the protein is synthesized with an N-terminal mitochondrial targeting sequence that directs it to mitochondria where it functions.

TXNRD2 catalyzes the NADPH-dependent transfer of electrons to thioredoxin 2 (TXN2) via FAD, enabling the reduction of disulfide bonds in mitochondrial proteins. Through this reaction, TXNRD2 supports the mitochondrial thioredoxin system, helps maintain redox homeostasis, and contributes to antioxidant defense by enabling the regeneration of peroxiredoxins and other redox-regulated proteins. This activity is important for mitochondrial function, signaling, and the regulation of apoptosis under oxidative stress.

Structurally, TXNRD2 has the characteristic three-domain organization of mammalian thioredoxin reductases, including FAD- and NADPH-binding regions and a C-terminal redox-active disulfide that contains a selenocysteine residue. As a selenoprotein, TXNRD2 requires the incorporation of selenocysteine during translation, guided by a SECIS element in the 3' untranslated region.

Expression of TXNRD2 is widespread, with notable levels in tissues with high mitochondrial activity such as the heart, brain, liver, and kidney. Its expression and activity are influenced by oxidative stress and selenium status, reflecting its role in maintaining mitochondrial redox balance.

Clinical relevance includes evidence from mouse models where TXNRD2 disruption leads to embryonic lethality with cardiomyopathy due to oxidative damage. In humans, variants and reduced activity have been reported in association with cardiomyopathy in some studies, though contributions to disease risk remain under investigation. TXNRD2 is also investigated as a therapeutic target in cancer, where inhibitors of thioredoxin reductases aim to elevate oxidative stress in cancer cells.