Mitochondrial Targets for Pharmacological Intervention in Human Disease

Over the past several years, mitochondrial
dysfunction has been
linked to an increasing number of human illnesses, making mitochondrial
proteins (MPs) an ever more appealing target for therapeutic intervention.
With 20% of the mitochondrial proteome (312 of an estimated 1500 MPs)
having known interactions with small molecules, MPs appear to be highly
targetable. Yet, despite these targeted proteins functioning in a
range of biological processes (including induction of apoptosis, calcium
homeostasis, and metabolism), very few of the compounds targeting
MPs find clinical use. Recent work has greatly expanded the number
of proteins known to localize to the mitochondria and has generated
a considerable increase in MP 3D structures available in public databases,
allowing experimental screening and in silico prediction of mitochondrial
drug targets on an unprecedented scale. Here, we summarize the current
literature on clinically active drugs that target MPs, with a focus
on how existing drug targets are distributed across biochemical pathways
and organelle substructures. Also, we examine current strategies for
mitochondrial drug discovery, focusing on genetic, proteomic, and
chemogenomic assays, and relevant model systems. As cell models and
screening techniques improve, MPs appear poised to emerge as relevant
targets for a wide range of complex human diseases, an eventuality
that can be expedited through systematic analysis of MP function.