Natural Product Screening Reveals Naphthoquinone Complex I Bypass Factors
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CitationVafai, Scott B., Emily Mevers, Kathleen W. Higgins, Yevgenia Fomina, Jianming Zhang, Anna Mandinova, David Newman, Stanley Y. Shaw, Jon Clardy, and Vamsi K. Mootha. 2016. “Natural Product Screening Reveals Naphthoquinone Complex I Bypass Factors.” PLoS ONE 11 (9): e0162686. doi:10.1371/journal.pone.0162686. http://dx.doi.org/10.1371/journal.pone.0162686.
AbstractDeficiency of mitochondrial complex I is encountered in both rare and common diseases, but we have limited therapeutic options to treat this lesion to the oxidative phosphorylation system (OXPHOS). Idebenone and menadione are redox-active molecules capable of rescuing OXPHOS activity by engaging complex I-independent pathways of entry, often referred to as “complex I bypass.” In the present study, we created a cellular model of complex I deficiency by using CRISPR genome editing to knock out Ndufa9 in mouse myoblasts, and utilized this cell line to develop a high-throughput screening platform for novel complex I bypass factors. We screened a library of ~40,000 natural product extracts and performed bioassay-guided fractionation on a subset of the top scoring hits. We isolated four plant-derived 1,4-naphthoquinone complex I bypass factors with structural similarity to menadione: chimaphilin and 3-chloro-chimaphilin from Chimaphila umbellata and dehydro-α-lapachone and dehydroiso-α-lapachone from Stereospermum euphoroides. We also tested a small number of structurally related naphthoquinones from commercial sources and identified two additional compounds with complex I bypass activity: 2-methoxy-1,4-naphthoquinone and 2-methoxy-3-methyl-1,4,-naphthoquinone. The six novel complex I bypass factors reported here expand this class of molecules and will be useful as tool compounds for investigating complex I disease biology.
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