NAD supplementation improves mitochondrial performance of cardiolipin mutants |
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| Affiliation: | 1. Department of Biological Sciences, College of Liberal Arts and Sciences, Wayne State University, Detroit, MI, United States of America;2. Department of Physiology, Wayne State University School of Medicine, Detroit, MI, United States of America;3. Department of Emergency Medicine, Wayne State University School of Medicine, Detroit, MI, United States of America;4. Department of Biotechnology, University of Rijeka, Radmile Matejcic 2, 51000 Rijeka, Croatia;1. Group on Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada;2. Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada;3. Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada;4. Department of Cell Biology, University of Alberta, Edmonton, Alberta, Canada;1. Institute of Molecular Enzyme Technology, Heinrich Heine University Düsseldorf, Forschungszentrum Jülich GmbH, D-52425 Jülich, Germany;2. Institute of Biochemistry, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany;3. Department of Microbiology and Biotechnology, University of Hamburg, Ohnhorststr. 18, 22609 Hamburg, Germany;4. Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany;5. Centro de Bioinformática y Simulación Molecular (CBSM), Facultad de Ingeniería, Universidad de Talca, 2 Norte 685, CL-3460000 Talca, Chile;6. Synthetic Membrane Systems, Institute of Biochemistry, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany;7. John von Neumann Institute for Computing (NIC), Jülich Supercomputing Centre (JSC), Institute of Biological Information Processing (IBI-7: Structural Biochemistry) & Institute of Bio- and Geosciences (IBG-4: Bioinformatics), Forschungszentrum Jülich GmbH, 52425 Jülich, Germany;8. Institute of Bio- and Geosciences, Plant Sciences (IBG-2) and Agrosphere (IBG-3), Forschungszentrum Jülich GmbH, D-52425 Jülich, Germany;1. Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan;2. Laboratory of Molecular Biology, Azabu University School of Veterinary Medicine, Sagamihara 252-5201, Japan;3. Laboratory of Farm Animal Internal Medicine, Azabu University School of Veterinary Medicine, Sagamihara 252-5201, Japan;4. Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama 526-0829, Japan;5. Laboratory of Veterinary Pharmacology, Azabu University School of Veterinary Medicine, Sagamihara 252-5201, Japan;1. Group on the Molecular and Cell Biology of Lipids, Canada;2. Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada;3. Department of Pediatrics, University of Alberta, Edmonton, Alberta T6G 2S2, Canada;4. Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2S2, Canada;5. Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada;6. Department of Cell Biology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada |
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| Abstract: | Cardiolipin (CL) deficiency causes mitochondrial dysfunction and aberrant metabolism that are associated in humans with the severe disease Barth syndrome (BTHS). Several metabolic abnormalities are observed in BTHS patients and model systems, including decreased oxidative phosphorylation, reduced tricarboxylic acid (TCA) cycle flux, and accumulated lactate and D-β-hydroxybutyrate, which strongly suggests that nicotinamide adenine dinucleotide (NAD) redox metabolism may be altered in CL-deficient cells. In this study, we identified abnormal NAD+ metabolism in multiple BTHS model systems and demonstrate that supplementation of NAD+ precursors such as nicotinamide mononucleotide (NMN) improves mitochondrial function. Improved mitochondrial function in the Drosophila model was associated with restored exercise endurance, which suggests a potential therapeutic benefit of NAD+ precursor supplementation in the management of BTHS patients. |
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