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Mitochondrial NADP(H) generation is essential for proline biosynthesis.

ABSTRACT: The coenzyme nicotinamide adenine dinucleotide phosphate (NADP⁺) and its reduced form (NADPH) regulate reductive metabolism in a subcellularly compartmentalized manner. Mitochondrial NADP(H) production depends on the phosphorylation of NAD(H) by NAD kinase 2 (NADK2). Deletion of NADK2 in human cell lines did not alter mitochondrial folate pathway activity, tricarboxylic acid cycle activity, or mitochondrial oxidative stress, but rather led to impaired cell proliferation in minimal medium. This growth defect was rescued by proline supplementation. NADK2-mediated mitochondrial NADP(H) generation was required for the reduction of glutamate and hence proline biosynthesis. Furthermore, mitochondrial NADP(H) availability determined the production of collagen proteins by cells of mesenchymal lineage. Thus, a primary function of the mitochondrial NADP(H) pool is to support proline biosynthesis for use in cytosolic protein synthesis.

SUBMITTER: Zhu J

PROVIDER: S-EPMC8241437 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Mitochondrial NADP(H) generation is essential for proline biosynthesis.

Zhu Jiajun J Schwörer Simon S Berisa Mirela M Kyung Yeon Ju YJ Ryu Keun Woo KW Yi Junmei J Jiang Xuejun X Cross Justin R JR Thompson Craig B CB

Science (New York, N.Y.) 20210422 6545

The coenzyme nicotinamide adenine dinucleotide phosphate (NADP+) and its reduced form (NADPH) regulate reductive metabolism in a subcellularly compartmentalized manner. Mitochondrial NADP(H) production depends on the phosphorylation of NAD(H) by NAD kinase 2 (NADK2). Deletion of NADK2 in human cell lines did not alter mitochondrial folate pathway activity, tricarboxylic acid cycle activity, or mitochondrial oxidative stress, but rather led to impaired cell proliferation in mini ...[more]

PMID: 33888598

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