Mitochondrial NADP(H) generation is essential for proline biosynthesis.
Jiajun Zhu1, Simon Schwörer1, Mirela Berisa2
1Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Science (New York, N.Y.)
|April 23, 2021
Summary
Mitochondrial NAD kinase 2 (NADK2) generates NADP(H) essential for proline biosynthesis and collagen production. Its absence impairs cell growth, which proline supplementation rescues.
Area of Science:
- Biochemistry
- Cell Biology
- Metabolic Regulation
Background:
- Nicotinamide adenine dinucleotide phosphate (NADP+) and its reduced form (NADPH) are crucial coenzymes for reductive metabolism.
- Mitochondrial NADP(H) homeostasis is vital for cellular functions, with NAD kinase 2 (NADK2) identified as a key producer.
Purpose of the Study:
- To investigate the specific role of mitochondrial NADP(H) generated by NADK2 in cellular metabolism and proliferation.
- To elucidate the impact of NADK2 deficiency on key metabolic pathways and cellular functions.
Main Methods:
- Utilized human cell lines with NADK2 deletion.
- Assessed mitochondrial folate and tricarboxylic acid cycle activity.
- Monitored cell proliferation, oxidative stress, proline biosynthesis, and collagen production.
Main Results:
- NADK2 deletion impaired cell proliferation in minimal medium, a defect rescued by proline supplementation.
- Mitochondrial NADP(H) generation by NADK2 is essential for glutamate reduction and subsequent proline biosynthesis.
- NADP(H) availability in mitochondria influences collagen protein synthesis in mesenchymal cells.
Conclusions:
- Mitochondrial NADK2-dependent NADP(H) production is critical for proline biosynthesis, supporting cytosolic protein synthesis.
- The mitochondrial NADP(H) pool plays a significant role in collagen production by mesenchymal cells.
- NADK2 is a key regulator of cellular growth and biosynthetic processes through its control of mitochondrial NADP(H).
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