Natural Product Screening Reveals Naphthoquinone Complex I Bypass Factors.
Deficiency 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 com...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2016-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5021346?pdf=render |
| _version_ | 1819094833955864576 |
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| author | Scott B Vafai Emily Mevers Kathleen W Higgins Yevgenia Fomina Jianming Zhang Anna Mandinova David Newman Stanley Y Shaw Jon Clardy Vamsi K Mootha |
| author_facet | Scott B Vafai Emily Mevers Kathleen W Higgins Yevgenia Fomina Jianming Zhang Anna Mandinova David Newman Stanley Y Shaw Jon Clardy Vamsi K Mootha |
| author_sort | Scott B Vafai |
| collection | DOAJ |
| description | Deficiency 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. |
| first_indexed | 2024-12-21T23:33:42Z |
| format | Article |
| id | doaj.art-1189c546b7fa4d0dbe61eebbf1fa260a |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-21T23:33:42Z |
| publishDate | 2016-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-1189c546b7fa4d0dbe61eebbf1fa260a2022-12-21T18:46:25ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-01119e016268610.1371/journal.pone.0162686Natural Product Screening Reveals Naphthoquinone Complex I Bypass Factors.Scott B VafaiEmily MeversKathleen W HigginsYevgenia FominaJianming ZhangAnna MandinovaDavid NewmanStanley Y ShawJon ClardyVamsi K MoothaDeficiency 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.http://europepmc.org/articles/PMC5021346?pdf=render |
| spellingShingle | Scott B Vafai Emily Mevers Kathleen W Higgins Yevgenia Fomina Jianming Zhang Anna Mandinova David Newman Stanley Y Shaw Jon Clardy Vamsi K Mootha Natural Product Screening Reveals Naphthoquinone Complex I Bypass Factors. PLoS ONE |
| title | Natural Product Screening Reveals Naphthoquinone Complex I Bypass Factors. |
| title_full | Natural Product Screening Reveals Naphthoquinone Complex I Bypass Factors. |
| title_fullStr | Natural Product Screening Reveals Naphthoquinone Complex I Bypass Factors. |
| title_full_unstemmed | Natural Product Screening Reveals Naphthoquinone Complex I Bypass Factors. |
| title_short | Natural Product Screening Reveals Naphthoquinone Complex I Bypass Factors. |
| title_sort | natural product screening reveals naphthoquinone complex i bypass factors |
| url | http://europepmc.org/articles/PMC5021346?pdf=render |
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