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ID: ALA4665824
Journal: J Med Chem
Title: Characterization and Discovery of a Selective Small-Molecule Modulator of Mitochondrial Complex I Targeting a Unique Binding Site.
Authors: Green JC,Jiang Y,He L,Xu Y,Sun D,Keoprasert T,Nelson C,Oh U,Lesnefsky EJ,Kellogg GE,Chen Q,Zhang S
Abstract: Mitochondrial dysfunction has been recognized as an essential contributor to many human diseases including neurodegenerative disorders. However, the exact pathological role of mitochondrial dysfunction, especially in mitochondrial reactive oxygen species-associated oxidative stress, remains elusive, partially due to the lack of chemical probes with well-defined mechanisms of action. Herein, we describe the characterization and discovery of a rationally designed small molecule ZCM-I-1 as a selective modulator of the production of reactive oxygen species from mitochondrial complex I that does not alter mitochondrial membrane potential and bioenergetics. Chemical biology studies employing photoaffinity probes derived from ZCM-I-1 demonstrated its novel mechanism of action of modulating complex I via interactions with the flavin mononucleotide site, proximal in the reaction pathway within complex I.
CiteXplore: 32945676