NNT gene: Nicotinamide Nucleotide Transhydrogenase – function, mutations, and disease associations

The NNT gene encodes nicotinamide nucleotide transhydrogenase, a mitochondrial inner membrane protein that catalyzes the transfer of a hydride ion from NADH to NADP+ to produce NADPH. This reaction is coupled to the proton gradient across the mitochondrial membrane. NADPH is essential for antioxidant defense (e.g., regeneration of glutathione and thioredoxin), steroidogenesis, and other biosynthetic pathways. Mutations in NNT cause familial glucocorticoid deficiency type 4 and have been associated with primary hyperoxaluria and other metabolic disorders.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• NADPH regeneration (mitochondrial)

• Glutathione metabolism

• Steroid hormone biosynthesis

• Pentose phosphate pathway (indirect)

Nicotinamide nucleotide transhydrogenase (NNT) is a 1086-amino-acid mitochondrial inner membrane protein. It uses the proton motive force to catalyze the reversible transfer of a hydride from NADH to NADP+, generating NADPH. NADPH is critical for mitochondrial antioxidant systems (e.g., glutathione reductase, thioredoxin reductase) and for cytochrome P450-dependent steroidogenesis. NNT deficiency leads to increased oxidative stress and impaired cortisol synthesis, causing familial glucocorticoid deficiency.