Characterization and Discovery of a Selective Small-Molecule Modulator of Mitochondrial Complex I Targeting a Unique Binding Site

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.