Mitochondrial NADP(H) generation is essential for proline biosynthesis

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Science  28 May 2021:
Vol. 372, Issue 6545, pp. 968-972
DOI: 10.1126/science.abd5491

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Providing for protein synthesis

Compartmentalization of metabolic processes into organelles can have important consequences. Zhu et al. examined the role of the coenzyme nicotinamide adenine dinucleotide phosphate (NADP+) and its reduced form (NADPH) in cultured human cells. They found that cells lacking NAD kinase 2, an enzyme needed to make NADPH, had decreased abundance of mitochondrial NADPH and proliferated slowly in culture medium with limited nutrients because of a lack of proline. Proline is made in the mitochondria, and thus a key function of NADPH in the mitochondria appears to be the synthesis of proline to sustain cellular protein synthesis.

Science, abd5491, this issue p. 968


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.

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