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Identification of a novel mitochondrial uncoupler that does not depolarize the plasma membrane

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dc.contributor.authorKenwood, Brandon M.en
dc.contributor.authorWeaver, Janelle L.en
dc.contributor.authorBajwa, Amandeepen
dc.contributor.authorPoon, Ivan K.en
dc.contributor.authorByrne, Frances L.en
dc.contributor.authorMurrow, Beverley A.en
dc.contributor.authorCalderone, Joseph A.en
dc.contributor.authorHuang, Lipingen
dc.contributor.authorDivakaruni, Ajit S.en
dc.contributor.authorTomsig, Jose L.en
dc.contributor.authorOkabe, Kohkien
dc.contributor.authorLo, Ryan H.en
dc.contributor.authorColeman, G. Cameronen
dc.contributor.authorColumbus, Lindaen
dc.contributor.authorYan, Zhenen
dc.contributor.authorSaucerman, Jeffrey J.en
dc.contributor.authorSmith, Jeffrey S.en
dc.contributor.authorHolmes, Jeffrey W.en
dc.contributor.authorLynch, Kevin R.en
dc.contributor.authorRavichandran, Kodi S.en
dc.contributor.authorUchiyama, Seiichien
dc.contributor.authorSantos, Webster L.en
dc.contributor.authorRogers, George W.en
dc.contributor.authorOkusa, Mark D.en
dc.contributor.authorBayliss, Douglas A.en
dc.contributor.authorHoehn, Kyle L.en
dc.contributor.departmentChemistryen
dc.contributor.departmentCenter for Drug Discoveryen
dc.date.accessioned2020-09-01T17:47:23Zen
dc.date.available2020-09-01T17:47:23Zen
dc.date.issued2013en
dc.description.abstractDysregulation of oxidative phosphorylation is associated with increased mitochondrial reactive oxygen species production and some of the most prevalent human diseases including obesity, cancer, diabetes, neurodegeneration, and heart disease. Chemical 'mitochondrial uncouplers' are lipophilic weak acids that transport protons into the mitochondrial matrix via a pathway that is independent of ATP synthase, thereby uncoupling nutrient oxidation from ATP production. Mitochondrial uncouplers also lessen the proton motive force across the mitochondrial inner membrane and thereby increase the rate of mitochondrial respiration while decreasing production of reactive oxygen species. Thus, mitochondrial uncouplers are valuable chemical tools that enable the measurement of maximal mitochondrial respiration and they have been used therapeutically to decrease mitochondrial reactive oxygen species production. However, the most widely used protonophore uncouplers such as carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) and 2,4-dinitrophenol have off-target activity at other membranes that lead to a range of undesired effects including plasma membrane depolarization, mitochondrial inhibition, and cytotoxicity. These unwanted properties interfere with the measurement of mitochondrial function and result in a narrow therapeutic index that limits their usefulness in the clinic. To identify new mitochondrial uncouplers that lack off-target activity at the plasma membrane we screened a small molecule chemical library. Herein we report the identification and validation of a novel mitochondrial protonophore uncoupler (2-fluorophenyl){6-[(2-fluorophenyl)amino](1,2,5-oxadiazolo[3,4-e]pyrazin-5-yl)}amine, named BAM15, that does not depolarize the plasma membrane. Compared to FCCP, an uncoupler of equal potency, BAM15 treatment of cultured cells stimulates a higher maximum rate of mitochondrial respiration and is less cytotoxic. Furthermore, BAM15 is bioactive in vivo and dose-dependently protects mice from acute renal ischemic-reperfusion injury. From a technical standpoint, BAM15 represents an effective new tool that allows the study of mitochondrial function in the absence of off-target effects that can confound data interpretation. From a therapeutic perspective, BAM15-mediated protection from ischemia-reperfusion injury and its reduced toxicity will hopefully reignite interest in pharmacological uncoupling for the treatment of the myriad of diseases that are associated with altered mitochondrial function.en
dc.description.sponsorshipThis work was funded through start-up funds provided by the Department of Pharmacology at the University of Virginia (KLH), the American Diabetes Association (1-11-JF-17, KLH), and the University of Virginia Launchpad Biomedical Innovation in Diabetes Fund (KLH).en
dc.format.extent10 pagesen
dc.format.mimetypeapplication/pdfen
dc.identifier.urihttp://hdl.handle.net/10919/99880en
dc.identifier.volume3en
dc.language.isoenen
dc.publisherElsevieren
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectMitochondriaen
dc.subjectBioenergeticsen
dc.subjectFCCPen
dc.subjectCCCPen
dc.subjectDNPen
dc.subjectIschemiaen
dc.titleIdentification of a novel mitochondrial uncoupler that does not depolarize the plasma membraneen
dc.title.serialMolecular Metabolismen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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