NNT (gene)
NNT is the gene that encodes the mitochondrial enzyme nicotinamide nucleotide transhydrogenase. In humans, the NNT gene sits on chromosome 5 and has 26 exons, producing a protein about 109 kDa in size. There are two alternative splice variants that make the same protein.
What it does: NAD(P) transhydrogenase sits in the inner mitochondrial membrane and links the transfer of a hydride between NADH and NADP+ with proton movement across the membrane. This activity, powered by the mitochondrial proton gradient, generates NADPH inside mitochondria, a key reducing agent used for biosynthesis and, importantly, for defending mitochondria against reactive oxygen species by maintaining a healthy glutathione balance. The enzyme can adopt open and occluded conformations during its catalytic cycle, and its dII subunit spans the inner membrane.
Why it matters clinically: Proper NNT function supports heart energy production and oxidative stress defense. In heart disease, partial loss of NNT activity can impair mitochondrial NADPH production and proton gradient maintenance, potentially worsening energy production and oxidative damage. Mutations in NNT are linked to familial glucocorticoid deficiency type 1 (FGD1), an autosomal recessive condition where the adrenal cortex fails to respond to ACTH, leading to cortisol deficiency and symptoms such as hypoglycemia, poor growth, infections, and shock.
Model systems: The common mouse strain C57BL/6J carries Nnt mutations, making it a useful model for studying NNT’s role in diabetes and metabolism.
Expression: NNT is widely expressed in humans, with high levels in the heart (including the right and left ventricles) and various muscles, and notable expression in the kidney and during embryonic development.
This page was last edited on 2 February 2026, at 14:06 (CET).