Instability in NAD+ metabolism leads to impaired cardiac mitochondrial function and communication.
Elife
; 102021 08 03.
Article
em En
| MEDLINE
| ID: mdl-34343089
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.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
DNA Mitocondrial
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Reparo do DNA
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Coração
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Cardiopatias
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Miocárdio
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NAD
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article