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

Autor:	Lauritzen KH; Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet and University of Oslo, Oslo, Norway., Olsen MB; Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet and University of Oslo, Oslo, Norway., Ahmed MS; Institute for Surgical Research, Oslo University Hospital and University of Oslo, Oslo, Norway., Yang K; Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet and University of Oslo, Oslo, Norway., Rinholm JE; Department of Microbiology, Oslo University Hospital, Oslo, Norway., Bergersen LH; Department of Oral Biology, University of Oslo, Oslo, Norway.; Department of Neuroscience and Pharmacology, Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark., Esbensen QY; Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Nordbyhagen, Norway., Sverkeli LJ; Department of Biomedicine, University of Bergen, Bergen, Norway., Ziegler M; Department of Biomedicine, University of Bergen, Bergen, Norway., Attramadal H; Institute for Surgical Research, Oslo University Hospital and University of Oslo, Oslo, Norway., Halvorsen B; 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., Aukrust P; 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., Yndestad A; 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.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2021 Aug 03; Vol. 10. Date of Electronic Publication: 2021 Aug 03.
DOI:	10.7554/eLife.59828
Abstrakt:	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. Competing Interests: KL, MO, MA, KY, JR, LB, QE, LS, MZ, HA, BH, PA, AY No competing interests declared (© 2021, Lauritzen et al.)
Databáze:	MEDLINE
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