Ubiquinone-binding site mutagenesis reveals the role of mitochondrial complex II in cell death initiation

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11310%2F15%3A10295023" target="_blank" >RIV/00216208:11310/15:10295023 - isvavai.cz</a>

Alternative codes found

RIV/86652036:_____/15:00446618 RIV/67985823:_____/15:00446618

Result on the web

<a href="http://dx.doi.org/10.1038/cddis.2015.110" target="_blank" >http://dx.doi.org/10.1038/cddis.2015.110</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/cddis.2015.110" target="_blank" >10.1038/cddis.2015.110</a>

Result language

angličtina

Original language name

Ubiquinone-binding site mutagenesis reveals the role of mitochondrial complex II in cell death initiation

Original language description

Respiratory complex II (CII, succinate dehydrogenase, SDH) inhibition can induce cell death, but the mechanistic details need clarification. To elucidate the role of reactive oxygen species (ROS) formation upon the ubiquinone-binding (Qp) site blockade, we substituted CII subunit C (SDHC) residues lining the Qp site by site-directed mutagenesis. Cell lines carrying these mutations were characterized on the bases of CII activity and exposed to Qp site inhibitors MitoVES, thenoyltrifluoroacetone (TTFA) and Atpenin A5. We found that I56F and S68A SDHC variants, which support succinate-mediated respiration and maintain low intracellular succinate, were less efficiently inhibited by MitoVES than the wild-type (WT) variant. Importantly, associated ROS generation and cell death induction was also impaired, and cell death in the WT cells was malonate and catalase sensitive. In contrast, the S68A variant was much more susceptible to TTFA inhibition than the I56F variant or the WT CII, which was again reflected by enhanced ROS formation and increased malonate- and catalase-sensitive cell death induction. The R72C variant that accumulates intracellular succinate due to compromised CII activity was resistant to MitoVES and TTFA treatment and did not increase ROS, even though TTFA efficiently generated ROS at low succinate in mitochondria isolated from R72C cells. Similarly, the high-affinity Qp site inhibitor Atpenin A5 rapidly increased intracellular succinate in WT cells but did not induce ROS or cell death, unlike MitoVES and TTFA that upregulated succinate only moderately. These results demonstrate that cell death initiation upon CII inhibition depends on ROS and that the extent of cell death correlates with the potency of inhibition at the Qp site unless intracellular succinate is high. In addition, this validates the Qp site of CII as a target for cell death induction with relevance to cancer therapy.

Czech name

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Czech description

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Type

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

CEP classification

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OECD FORD branch

10600 - Biological sciences

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

2015

Confidentiality

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

Name of the periodical

Cell death &amp; disease

ISSN

2041-4889

e-ISSN

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Volume of the periodical

6

Issue of the periodical within the volume

6

Country of publishing house

GB - UNITED KINGDOM

Number of pages

13

Pages from-to

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UT code for WoS article

000357513200014

EID of the result in the Scopus database

2-s2.0-84957308920