Instability in NAD+ metabolism leads to impaired cardiac mitochondrial function and communication

eLife

Lars Jansen Sverkeli¹  Mathias Ziegler¹  Qin Ying Esbensen²  Johanne Egge Rinholm³  Linda H Bergersen⁴  Håvard Attramadal⁵  Mohammed Shakil Ahmed⁵  Kuan Yang⁶  Knut H Lauritzen⁶  Maria Belland Olsen⁶  Arne Yndestad⁷  Bente Halvorsen⁷  Pål Aukrust⁸ 

[1] Department of Biomedicine, University of Bergen, Bergen, Norway;Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Nordbyhagen, Norway;Department of Microbiology, Oslo University Hospital, Oslo, Norway;Department of Oral Biology, University of Oslo, Oslo, Norway;Department of Neuroscience and Pharmacology, Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark;Institute for Surgical Research, Oslo University Hospital and University of Oslo, Oslo, Norway;Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet and University of Oslo, Oslo, Norway;Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet and University of Oslo, Oslo, Norway;Institute of Clinical Medicine, University of Oslo, Faculty of Medicine, Oslo, Norway;Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet and University of Oslo, Oslo, Norway;Institute of Clinical Medicine, University of Oslo, Faculty of Medicine, Oslo, Norway;Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway;

关键词: mitochondrial dna;    NAD;    cardiovascular disease;    nicotinamide riboside;    SIRT3;    DNA repair;    Human;    Mouse;   

DOI  :  10.7554/eLife.59828

来源: eLife Sciences Publications, Ltd

【 摘 要 】

Poly(ADP-ribose) polymerase (PARP) enzymes initiate (mt)DNA repair mechanisms and use nicotinamide adenine dinucleotide (NAD+) as energy source. Prolonged PARP activity can drain cellular NAD+ reserves, leading to de-regulation of important molecular processes. Here, we provide evidence of a pathophysiological mechanism that connects mtDNA damage to cardiac dysfunction via reduced NAD+ levels and loss of mitochondrial function and communication. Using a transgenic model, we demonstrate that high levels of mice cardiomyocyte mtDNA damage cause a reduction in NAD+ levels due to extreme DNA repair activity, causing impaired activation of NAD+-dependent SIRT3. In addition, we show that myocardial mtDNA damage in combination with high dosages of nicotinamideriboside (NR) causes an inhibition of sirtuin activity due to accumulation of nicotinamide (NAM), in addition to irregular cardiac mitochondrial morphology. Consequently, high doses of NR should be used with caution, especially when cardiomyopathic symptoms are caused by mitochondrial dysfunction and instability of mtDNA.

【 授权许可】

CC BY