Biochemical thresholds for pathological presentation of ATP synthase deficiencies

0523845 - FGÚ 2021 RIV US eng J - Journal Article
Nůsková, Hana - Mikešová, Jana - Efimova, Iuliia - Pecinová, Alena - Pecina, Petr - Drahota, Zdeněk - Houštěk, Josef - Mráček, Tomáš
Biochemical thresholds for pathological presentation of ATP synthase deficiencies.
Biochemical and Biophysical Research Communications. Roč. 521, č. 4 (2020), s. 1036-1041. ISSN 0006-291X. E-ISSN 1090-2104
R&D Projects: GA ČR(CZ) GA16-01813S; GA MZd(CZ) NV16-33018A
Institutional support: RVO:67985823
Keywords : ATP synthase * deficiency * reactive oxygen species * oxidative phosphorylation * threshold effect
OECD category: Biochemistry and molecular biology
Impact factor: 3.575, year: 2020
Method of publishing: Limited access
https://doi.org/10.1016/j.bbrc.2019.11.033

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.
Permanent Link: http://hdl.handle.net/11104/0308123