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Biochemical thresholds for pathological presentation of ATP synthase deficiencies
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SYSNO ASEP 0523845 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Biochemical thresholds for pathological presentation of ATP synthase deficiencies Author(s) Nůsková, Hana (FGU-C) RID, ORCID
Mikešová, Jana (FGU-C) RID, ORCID
Efimova, Iuliia (FGU-C)
Pecinová, Alena (FGU-C) RID, ORCID, SAI
Pecina, Petr (FGU-C) RID, ORCID
Drahota, Zdeněk (FGU-C) RID, ORCID
Houštěk, Josef (FGU-C) RID, ORCID
Mráček, Tomáš (FGU-C) RID, ORCIDSource Title Biochemical and Biophysical Research Communications. - : Elsevier - ISSN 0006-291X
Roč. 521, č. 4 (2020), s. 1036-1041Number of pages 6 s. Language eng - English Country US - United States Keywords ATP synthase ; deficiency ; reactive oxygen species ; oxidative phosphorylation ; threshold effect Subject RIV CE - Biochemistry OECD category Biochemistry and molecular biology R&D Projects GA16-01813S GA ČR - Czech Science Foundation (CSF) NV16-33018A GA MZd - Ministry of Health (MZ) Method of publishing Limited access Institutional support FGU-C - RVO:67985823 UT WOS 000507487200034 DOI 10.1016/j.bbrc.2019.11.033 Annotation Mitochondrial ATP synthase is responsible for production of the majority of cellular ATP. Disorders of ATP synthase in humans can be caused by numerous mutations in both structural subunits and specific assembly factors. They are associated with variable pathogenicity and clinical phenotypes ranging from mild to the most severe mitochondrial diseases. To shed light on primary/pivotal functional consequences of ATP synthase deficiency, we explored human HEK 293 cells with a varying content of fully assembled ATP synthase, selectively downregulated to 15-80% of controls by the knockdown of F-1 subunits gamma, delta and epsilon. Examination of cellular respiration and glycolytic flux revealed that enhanced glycolysis compensates for insufficient mitochondrial ATP production while reduced dissipation of mitochondrial membrane potential leads to elevated ROS production. Both insufficient energy provision and increased oxidative stress contribute to the resulting pathological phenotype. The threshold for manifestation of the ATP synthase defect and subsequent metabolic remodelling equals to 10-30% of residual ATP synthase activity. The metabolic adaptations are not able to sustain proliferation in a galactose medium, although sufficient under glucose-rich conditions. As metabolic alterations occur when the content of ATP synthase drops below 30%, some milder ATP synthase defects may not necessarily manifest with a mitochondrial disease phenotype, as long as the threshold level is not exceeded. Workplace Institute of Physiology Contact Lucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400 Year of Publishing 2021 Electronic address https://doi.org/10.1016/j.bbrc.2019.11.033
Number of the records: 1