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

ABSTRACT: 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 dosag

SUBMITTER: Lauritzen KH 

PROVIDER: S-EPMC8331182 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature