Antimycin A: From mitochondrial poison to multifaceted biological probe and therapeutic agent

Antimycin A is a member of a large family of depsipeptide natural products produced primarily by Streptomyces bacteria. First identified for its potent antifungal properties, it has become one of the most widely used and best-characterized inhibitors of cellular respiration. The canonical mechanism of Antimycin A involves high-affinity binding to the Qi site of the cytochrome bc 1 complex (Complex III) in the mitochondrial electron transport chain, effectively blocking electron flow and halting ATP synthesis via oxidative phosphorylation. This inhibition leads to a cascade of profound cellular consequences, most notably the massive production of superoxide radicals from the Complex III Qo site, induction of oxidative stress, and the initiation of cell death pathways such as apoptosis. However, decades of research have revealed that the biological activities of Antimycin A extend far beyond its role as a simple mitochondrial poison. It is a key modulator of complex cellular processes including autophagy and mitophagy, and a molecule with a surprisingly diverse and potent range of bioactivities. Recent studies have highlighted its potential as an anticancer agent that selectively targets tumor cells, a potential antifungal and antiviral therapy, and an indispensable chemical probe for investigating mitochondrial function and retrograde signaling. This review synthesizes the current understanding of Antimycin A, covering its biosynthesis and chemical diversity, its detailed molecular mechanism of action, its multifaceted impacts on cellular physiology in organisms from yeast to humans, and its expanding applications in both basic research and as a potential therapeutic agent.