Department of Microbiology, Oslo University Hospital, Oslo, Norway
Linda H Bergersen
Department of Oral Biology, University of Oslo, Oslo, Norway; Department of Neuroscience and Pharmacology, Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark
Qin Ying Esbensen
Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Nordbyhagen, Norway
Lars Jansen Sverkeli
Department of Biomedicine, University of Bergen, Bergen, 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
Pål Aukrust
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
Arne Yndestad
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
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.
