Redesigned Mito-ATO Analogs Bind the Qi Site of Mitochondrial Complex III in Cancer Cells
A collaboration among researchers in the MCW Departments of Biophysics (Balaraman Kalyanaraman, PhD, the Harry R. & Angeline E. Quadracci Professor in Parkinson’s Research; Gang Cheng, PhD, assistant professor; Vanessa A. Leone, PhD, assistant professor) and Aix-Marseille University in France (Micael Hardy, PhD; Gabriel Canard, PhD; Didier Siri, PhD; Bruna Pereira Resende, PhD candidate) resulted in a new publication titled “Redox and structural determinants of mitochondrial complex III inhibition by triphenylphosphonium-conjugated atovaquone analogs” in Redox Biology.
Cancer cells often rely on glycolysis for energy even when oxygen is available, a phenomenon called the Warburg effect. This was long attributed to defective mitochondria, but the Kalyanaraman laboratory, among others, has previously established that mitochondria remain functional and are promising targets. They have pioneered agents that target mitochondrial respiratory complexes, with mitochondria-targeted atovaquone (Mito-ATO) as one flagship agent.
Atovaquone (ATO) is an FDA-approved drug that inhibits mitochondrial complex III and is being evaluated for cancer treatment. In this study, the co-authors synthesized a new series of mitochondria-targeted atovaquone derivatives (MitoR-ATO) by adding either electron-withdrawing or electron-donating groups to the triphenylphosphonium (TPP+) portion of the compounds. TPP+ is the targeting moiety that facilitates diffusion of the agents through the negatively charged mitochondrial membrane.
The co-authors examined how these structural changes affected redox behavior, cancer cell proliferation, and mitochondrial oxygen consumption. For the first time with mitochondria-targeted compounds, computational studies also assessed their binding to mitochondrial complex III. Although the co-authors expected MitoR-ATO to bind the same complex III site as ATO (the Qo site), the studies showed it binds instead at the Qi site. This unexpected binding mode may help explain the differences observed in experimental findings.
The image shows the location of the mitochondrial electron transport chain and its complexes inside the mitochondrion, and the proposed site of interaction for the novel Mito-ATO derivatives, whose structures are shown.