Ataxia-Telangiectasia Mutated is located in cardiac mitochondria and impacts oxidative phosphorylation
Date
2019
Journal Title
Journal ISSN
Volume Title
Publisher
Springer Nature
Abstract
The absence of Ataxia-Telangiectasia mutated protein kinase (ATM) is associated with neurological, metabolic and cardiovascular defects. The protein has been associated with mitochondria and its absence results in mitochondrial dysfunction. Furthermore, it can be activated in the cytosol by mitochondrial oxidative stress and mediates a cellular anti-oxidant response through the pentose phosphate pathway (PPP). However, the precise location and function of ATM within mitochondria and its role in oxidative phosphorylation is still unknown. We show that ATM is found endogenously within cardiac myocyte mitochondria under normoxic conditions and is consistently associated with the inner mitochondrial membrane. Acute ex vivo inhibition of ATM protein kinase significantly decreased mitochondrial electron transfer chain complex I-mediated oxidative phosphorylation rate but did not decrease coupling efficiency or oxygen consumption rate during β-oxidation. Chemical inhibition of ATM in rat cardiomyoblast cells (H9c2) significantly decreased the excited-state autofluorescence lifetime of enzyme-bound reduced NADH and its phosphorylated form, NADPH (NAD(P)H; 2.77 ± 0.26 ns compared to 2.57 ± 0.14 ns in KU60019-treated cells). This suggests an interaction between ATM and the electron transfer chain in the mitochondria, and hence may have an important role in oxidative phosphorylation in terminally differentiated cells such as cardiomyocytes.
Description
CITATION: Blignaut, M., et al. 2019. Ataxia-Telangiectasia Mutated is located in cardiac mitochondria and impacts oxidative phosphorylation. Scientific Reports, 9:4782, doi:10.1038/s41598-019-41108-1.
The original publication is available at http://www.nature.com/srep
Publication of this article was funded by the Stellenbosch University Open Access Fund.
The original publication is available at http://www.nature.com/srep
Publication of this article was funded by the Stellenbosch University Open Access Fund.
Keywords
Ataxia telangiectasia, Mitochondrial pathology, Phosphorylation
Citation
Blignaut, M., et al. 2019. Ataxia-Telangiectasia Mutated is located in cardiac mitochondria and impacts oxidative phosphorylation. Scientific Reports, 9:4782, doi:10.1038/s41598-019-41108-1