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Nat. Cell Biol., 21 April 2025 | https://doi.org/10.1038/s41556-025-01655-4
Mitochondrial NADPH fuels mitochondrial fatty acid synthesis and lipoylation to power oxidative metabolism
Dohun Kim 1, Rushendhiran Kesavan 1, Kevin Ryu 1, Trishna Dey 1, Austin Marckx 2, Cameron Menezes 1, Prakash P. Praharaj 1, Stewart Morley 3, Bookyong Ko 1, Mona H. Soflaee 1, Harrison J. Tom 1, Harrison Brown 1, Hieu S. Vu 1, Shih-Chia Tso 4, Chad A. Brautigam 4,5, Andrew Lemoff 6, Marcel Mettlen 7, Prashant Mishra 1, Feng Cai 1, Doug K. Allen 3,8 & Gerta Hoxhaj 1,*
1Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
2Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
3Donald Danforth Plant Science Center, St. Louis, MO, USA.
4Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
5Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
6Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
7Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
8United States Department of Agriculture, Agriculture Research Service, St. Louis, MO, USA.
2Lyda Hill Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
3Donald Danforth Plant Science Center, St. Louis, MO, USA.
4Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
5Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
6Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
7Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
8United States Department of Agriculture, Agriculture Research Service, St. Louis, MO, USA.
*Corresponding author: correspondence to Gerta Hoxhaj
Abstract
Nicotinamide adenine dinucleotide phosphate (NADPH) is a vital electron donor essential for macromolecular biosynthesis and protection against oxidative stress. Although NADPH is compartmentalized within the cytosol and mitochondria, the specific functions of mitochondrial NADPH remain largely unexplored. Here we demonstrate that NAD+ kinase 2 (NADK2), the principal enzyme responsible for mitochondrial NADPH production, is critical for maintaining protein lipoylation, a conserved lipid modification necessary for the optimal activity of multiple mitochondrial enzyme complexes, including the pyruvate dehydrogenase complex. The mitochondrial fatty acid synthesis (mtFAS) pathway utilizes NADPH for generating protein-bound acyl groups, including lipoic acid. By developing a mass-spectrometry-based method to assess mammalian mtFAS, we reveal that NADK2 is crucial for mtFAS activity. NADK2 deficiency impairs mtFAS-associated processes, leading to reduced cellular respiration and mitochondrial translation. Our findings support a model in which mitochondrial NADPH fuels the mtFAS pathway, thereby sustaining protein lipoylation and mitochondrial oxidative metabolism.
논문정보
- Research article
- 2025년 04월 (BRIC 등록일 2025-04-24)
- 국외 연구진
- 생명과학 > 생화학
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