Mitochondrial NADP(H) integrates redox and metabolism

Ren Zhang; Kezhong Zhang

doi:10.1016/j.tem.2025.12.003

Mitochondrial NADP(H) integrates redox and metabolism

Trends Endocrinol Metab. 2026 Mar 25:S1043-2760(25)00267-X. doi: 10.1016/j.tem.2025.12.003. Online ahead of print.

Authors

Ren Zhang¹, Kezhong Zhang²

Affiliations

¹ Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA. Electronic address: rzhang@med.wayne.edu.
² Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.

PMID: 41887981
PMCID: PMC13137535 (available on 2027-03-25)
DOI: 10.1016/j.tem.2025.12.003

Abstract

The compartmentalization of NAD(H) and NADP(H) is fundamental to cellular metabolism, enabling precise coordination of redox balance, biosynthetic reactions, and energy homeostasis. Within mitochondria, NADP(H) has long been viewed as a redox buffer supporting antioxidant defense and reductive biosynthesis. Emerging evidence, however, reveals that mitochondrial NADP(H) also drives oxidative metabolism and metabolic flexibility. Loss of the mitochondrial NAD kinase, which phosphorylates NAD(H) to generate mitochondrial NADP(H), disrupts NADP(H)-dependent pathways that sustain oxidative metabolism and systemic energy balance. These advances reposition mitochondrial NADP(H) as an integrative regulator that links redox homeostasis with energy metabolism across cellular and systemic levels, with broad implications for metabolic disease.

Keywords: NAD(H); NADK2; NADP(H); fatty acid oxidation; mitochondria; redox.

Publication types

Review

Grants and funding

R01 DK132065/DK/NIDDK NIH HHS/United States