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

Autor: Kenwood BM; Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA., Weaver JL; Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA., Bajwa A; Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA., Poon IK; Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA., Byrne FL; Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA., Murrow BA; Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA., Calderone JA; Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, USA., Huang L; Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA., Divakaruni AS; Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA., Tomsig JL; Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA., Okabe K; University of Tokyo, Tokyo, Japan., Lo RH; Department of Chemistry, University of Virginia, Charlottesville, VA 22908, USA., Cameron Coleman G; Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA., Columbus L; Department of Chemistry, University of Virginia, Charlottesville, VA 22908, USA., Yan Z; Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA ; Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA ; Department of Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA., Saucerman JJ; Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA ; Department of Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA., Smith JS; Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA., Holmes JW; Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA ; Department of Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA., Lynch KR; Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA., Ravichandran KS; Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA., Uchiyama S; University of Tokyo, Tokyo, Japan., Santos WL; Department of Chemistry and Virginia Tech Center for Drug Discovery, Virginia Tech, Blacksburg, VA 24061, USA., Rogers GW; Seahorse Bioscience, North Billerica, MA 01862, USA., Okusa MD; Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA., Bayliss DA; Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA., Hoehn KL; Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA ; Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA ; Department of Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA ; Emily Couric Clinical Cancer Center, University of Virginia, Charlottesville, VA 22908, USA.
Jazyk: angličtina
Zdroj: Molecular metabolism [Mol Metab] 2013 Nov 28; Vol. 3 (2), pp. 114-23. Date of Electronic Publication: 2013 Nov 28 (Print Publication: 2014).
DOI: 10.1016/j.molmet.2013.11.005
Abstrakt: Dysregulation 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.
Databáze: MEDLINE
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