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Abstract

Short-chain quinones (SCQs) have been investigated as potential therapeutic candidates against mitochondrial dysfunction, which was largely thought to be associated with the reversible redox characteristics of their active quinone core. We recently reported a library of SCQs, some of which showed potent cytoprotective activity against the mitochondrial complex I inhibitor rotenone in the human hepatocarcinoma cell line HepG2. To better characterize the cytoprotection of SCQs at a molecular level, a bioactivity profile for 103 SCQs with different compound chemistries was generated that included metabolism related markers, redox activity, expression of cytoprotective proteins and oxidative damage. Of all the tested endpoints, a positive correlation with cytoprotection by SCQs in the presence of rotenone was only observed for the NAD(P)H:quinone oxidoreductase 1 (NQO1)-dependent reduction of SCQs, which also correlated with an acute rescue of ATP levels. The results of this study suggest an unexpected mode of action for SCQs that appears to involve a modification of NQO1-dependent signaling rather than a protective effect by the reduced quinone itself. This finding presents a new selection strategy to identify and develop the most promising compounds towards their clinical use.

Item Type:	Article
Authors/Creators:	Feng, ZK and Nadikudi, M and Woolley, KL and Hemasa, AL and Chear, S and Smith, JA and Gueven, N
Keywords:	mitochondrial dysfunction, short-chain quinone, bioactivity, cytoprotection
Journal or Publication Title:	Molecules
Publisher:	Molecular Diversity Preservation International
ISSN:	1420-3049
DOI / ID Number:	10.3390/molecules26051382
Copyright Information:	Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International (CC BY 4.0) license (https://creativecommons.org/licenses/by/4.0/).
Related URLs:	UTAS Profile: Woolley, KL Google Scholar: Smith, JA UTAS Profile: Smith, JA Google Scholar: Gueven, N UTAS Profile: Gueven, N
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