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 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.
Highlights
Myocardial dysfunction leading to heart failure (HF) is an increasing health concern worldwide
We found increased Poly(ADP-ribose) polymerase (PARP) levels in isolated mitochondria from heart tissue from mutUNG1-expressing mice compared to wild-type (Wt) littermates (Figure 1A–B), accompanied by reduced total nicotinamide adenine dinucleotide (NAD)+ levels in cardiac tissue as assessed by HPLC (Figure 1C)
Sirtuins are dependent on NAD+ and SIRT3 is the major mitochondrial isoform that controls the activity of a number of different proteins through deacetylation
Summary
Myocardial dysfunction leading to heart failure (HF) is an increasing health concern worldwide. Agents that could maintain NAD+ levels could be an attractive therapeutic approach in disorders where increased PARP activity and decreased SIRT activity drive impaired mitochondrial function and increased mtDNA damage and cellular and tissue failure (Cheng et al, 2013; Karamanlidis et al, 2013). We demonstrate that high levels of cardiomyocyte mtDNA damage cause a reduction in NAD+ levels in heart tissue due to highly active DNA repair, and mitochondrial dysfunction due to loss of activation of crucial proteins involved in mitochondrial homeostasis. Our findings suggest that NR might have disadvantageous effects on cardiomyocyte mitochondria, at least in high dosages
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