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.
Highlights
Mitochondria are essential organelles involved in many cellular processes such as the control of cell death, Ca2+ -signaling as well as redox- and energy-homeostasis [1,2,3].Mitochondria provide about 95% of the cellular chemical energy in the form of adenosine triphosphate (ATP) via oxidative phosphorylation (OXPHOS)
The current study employed the previously reported endpoints of cytoprotection and normalization of cellular ATP levels [26], and assessed additional bioactivities of quinones that are indicative of mitochondrial function, compound bioactivation, expression or activities of cytoprotective proteins (Lin28A, Heat shock protein 70 (Hsp70), HDAC6), oxidative damage and DNA damage
While correlations obtained in vitro do not necessarily allow a direct translation to the in vivo situation, the current study aimed to provide a first unbiased insight into the molecular activities of shortchain quinones (SCQs) by utilizing a larger number of test compounds
Summary
Mitochondria are essential organelles involved in many cellular processes such as the control of cell death, Ca2+ -signaling as well as redox- and energy-homeostasis [1,2,3].Mitochondria provide about 95% of the cellular chemical energy in the form of adenosine triphosphate (ATP) via oxidative phosphorylation (OXPHOS). Mitochondria are essential organelles involved in many cellular processes such as the control of cell death, Ca2+ -signaling as well as redox- and energy-homeostasis [1,2,3]. Any insult or genetic predisposition that impairs mitochondrial function can lead to a range of mitochondrial diseases such as Leber’s hereditary optic neuropathy (LHON), Leigh syndrome (LS) and dominant optic atrophy (DOA) [4]. Mitochondrial dysfunction is present in a vast number of common inflammatory (i.e., ulcerative colitis) [5], neurodegenerative (i.e., Alzheimer’s disease, Parkinson’s disease, glaucoma, age-related macular degeneration) [6], neuromuscular (i.e., Duchenne muscular dystrophy, multiple sclerosis) [7], and metabolic disorders (i.e., diabetes, obesity) [8], which illustrates that mitochondrial pathology is widespread. This represents a significant unmet medical need and new drug candidates are needed that can be developed into effective and safe medications
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