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Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain
Author(s) -
Preston Sarah,
Korhonen Pasi K.,
Mouchiroud Laurent,
Cornaglia Matteo,
McGee Sean L.,
Young Neil D.,
Davis Rohan A.,
Crawford Simon,
Nowell Cameron,
Ansell Brendan R. E.,
Fisher Gillian M.,
Andrews Katherine T.,
Chang Bill C. H.,
Gijs Martin A. M.,
Sternberg Paul W.,
Auwerx Johan,
Baell Jonathan,
Hofmann Andreas,
Jabbar Abdul,
Gasser Robin B.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201700288r
Subject(s) - oxidative phosphorylation , respiratory chain , biology , phosphorylation , mitochondrial respiratory chain , mitochondrion , motility , biochemistry , chemistry , pharmacology , stereochemistry , microbiology and biotechnology
As a result of limited classes of anthelmintics and an over‐reliance on chemical control, there is a great need to discover new compounds to combat drug resistance in parasitic nematodes. Here, we show that deguelin, a plant‐derived rotenoid, selectively and potently inhibits the motility and development of nematodes, which supports its potential as a lead candidate for drug development. Furthermore, we demonstrate that deguelin treatment significantly increases gene transcription that is associated with energy metabolism, particularly oxidative phosphorylation and mitoribosomal protein production before inhibiting motility. Mitochondrial tracking confirmed enhanced oxidative phosphorylation. In accordance, real‐time measurements of oxidative phosphorylation in response to deguelin treatment demonstrated an immediate decrease in oxygen consumption in both parasitic ( Haemonchus contortus ) and free‐living ( Caenorhabditis elegans ) nematodes. Consequently, we hypothesize that deguelin is exerting its toxic effect on nematodes as a modulator of oxidative phosphorylation. This study highlights the dynamic biologic response of multicellular organisms to deguelin perturbation.—Preston, S., Korhonen, P. K., Mouchiroud, L., Cornaglia, M., McGee, S. L., Young, N. D., Davis, R. A., Crawford, S., Nowell, C., Ansell, B. R. E., Fisher, G. M., Andrews, K. T., Chang, B.C.H., Gijs, M.A.M., Sternberg, P.W., Auwerx, J., Baell, J., Hofmann, A., Jabbar, A., Gasser, R.B. Deguelin exerts potent nematocidal activity via the mitochondrial respiratory chain. FASEB J. 31, 4515–4532 (2017). www.fasebj.org