Mitochondrial Nicotinamide Nucleotide Transhydrogenase: Role in Energy Metabolism, Redox Homeostasis, and Cancer

Significance: Dimeric nicotinamide nucleotide transhydrogenase (NNT) is embedded in the mitochondrial inner membrane and couples the conversion of NADP⁺/NADH into NADPH/NAD⁺ to mitochondrial matrix proton influx. NNT was implied in various cancers, but its physiological role and regulation still remain incompletely understood. Recent Advances: NNT function was analyzed by studying: (1) NNT gene mutations in human (adrenal) glucocorticoid deficiency 4 (GCCD4), (2) Nnt gene mutation in C57BL/6J mice, and (3) the effect of NNT knockdown/overexpression in (cancer) cells. In these three models, altered NNT function induced both common and differential aberrations. Critical Issues: Information on NNT protein expression in GCCD4 patients is still scarce. Moreover, NNT expression levels are tissue-specific in humans and mice and the functional consequences of NNT deficiency strongly depend on experimental conditions. In addition, data from intact cells and isolated mitochondria are often unsuited for direct comparison. This prevents a proper understanding of NNT-linked (patho)physiology in GCCD4 patients, C57BL/6J mice, and cancer (cell) models, which complicates translational comparison. Future Directions: Development of mice with conditional NNT deletion, cell-reprogramming-based adrenal (organoid) models harboring specific NNT mutations, and/or NNT-specific chemical inhibitors/activators would be useful. Moreover, live-cell analysis of NNT substrate levels and mitochondrial/cellular functioning with fluorescent reporter molecules might provide novel insights into the conditions under which NNT is active and how this activity links to other metabolic and signaling pathways. This would also allow a better dissection of local signaling and/or compartment-specific (i.e., mitochondrial matrix, cytosol, nucleus) effects of NNT (dys)function in a cellular context. Antioxid. Redox Signal. 41, 927–956.