Biochemical thresholds for pathological presentation of ATP synthase deficiencies

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F20%3A00523845" target="_blank" >RIV/67985823:_____/20:00523845 - isvavai.cz</a>

Result on the web

<a href="https://doi.org/10.1016/j.bbrc.2019.11.033" target="_blank" >https://doi.org/10.1016/j.bbrc.2019.11.033</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.bbrc.2019.11.033" target="_blank" >10.1016/j.bbrc.2019.11.033</a>

Result language

angličtina

Original language name

Biochemical thresholds for pathological presentation of ATP synthase deficiencies

Original language description

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.

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10608 - Biochemistry and molecular biology

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2020

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Biochemical and Biophysical Research Communications

ISSN

0006-291X

e-ISSN

—

Volume of the periodical

521

Issue of the periodical within the volume

4

Country of publishing house

US - UNITED STATES

Number of pages

6

Pages from-to

1036-1041

UT code for WoS article

000507487200034

EID of the result in the Scopus database

—