title: Serendipity and the discovery of novel compounds that restore mitochondrial plasticity.
abstract: The mitochondrial electron transport chain (ETC) plays a central role in energy generation in the cell. Mitochondrial dysfunctions diminish adenosine triphosphate (ATP) production and result in insufficient energy to maintain cell function. As energy output declines, the most energetic tissues are preferentially affected. To satisfy cellular energy demands, the mitochondrial ETC needs to be able to elevate its capacity to produce ATP at times of increased metabolic demand or decreased fuel supply. This mitochondrial plasticity is reduced in many age-associated diseases. In this review, we describe the serendipitous discovery of a novel class of compounds that selectively target cardiolipin on the inner mitochondrial membrane to optimize efficiency of the ETC and thereby restore cellular bioenergetics in aging and diverse disease models, without any effect on the normal healthy organism. The first of these compounds, SS-31, is currently in multiple clinical trials.
authors.affiliation: Research Program in Mitochondrial Therapeutics, Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: H H
authors.initials: HH
authors.lastname: Szeto
authors.affiliation: Research Program in Mitochondrial Therapeutics, Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: A V
authors.initials: AV
authors.lastname: Birk
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000375:Aging / Q000378:metabolism; D002056:Burns / Q000188:drug therapy / Q000378:metabolism; D002308:Cardiolipins / Q000502:physiology; D045304:Cytochromes c / Q000378:metabolism; D055808:Drug Discovery; D004579:Electron Transport; D004734:Energy Metabolism / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D002308:Cardiolipins; D009842:Oligopeptides; C506540:arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide; D000255:Adenosine Triphosphate; D045304:Cytochromes c