Pharmacological modulation of mitochondrial dynamics: identification of a specific OPA1 inhibitor to enhance apoptotic release of cytochrome c.

The GTPase activity of OPA1, a dynamin-related mitochondrial protein upregulated in several tumors, controls cristae remodeling, cytochrome c release and apoptosis. To pharmacologically target OPA1 in cancer, we setup and iterated a high-throughput screening of a diversity based chemical library of 10,000 drug-like small molecules for recombinant purified OPA1 GTPase activity inhibition, identifying 8 candidates that were confirmed in a secondary screen. The most promising hit (MYLS22) was highly specific, as it could bind to recombinant OPA1 GTPase and did not inhibit recombinant Dynamin 1 GTPase activity. MYLS22 was not mitochondriotoxic, but it increased OPA1 oligomers disassembly and cytochrome c release in response to the proapoptotic stimulus BID in purified mitochondria and to hydrogen peroxide in cells, where MYLS22 caused the expected mitochondrial fragmentation. MYLS22 also phenocopied the inhibition of breast cancer cells migration caused by OPA1 silencing. Thus, we identified a first-in-kind OPA1 inhibitor with potential anti-cancer properties.