Targeting cytochrome C oxidase in mitochondria with Pt(II)-porphyrins for Photodynamic Therapy

摘要

Mitochondria are the power house of living cells, where the synthesis of thechemical "energy currency" adenosine triphosphate (ATP) occurs. Oxidativephosphorylation by a series of membrane protein complexes I to IV, that is, theelectron transport chain, is the source of the electrochemical potentialdifference or proton motive force (PMF) of protons across the innermitochondrial membrane. The PMF is required for ATP production by complex V ofthe electron transport chain, i.e. by FoF1-ATP synthase. Destroying cytochromeC oxidase (COX; complex IV) in Photodynamic Therapy (PDT) is achieved by thecationic photosensitizer Pt(II)-TMPyP. Electron microscopy revealed thedisruption of the mitochondrial christae as a primary step of PDT. Timeresolved phosphorescence measurements identified COX as the binding site forPt(II)-TMPyP in living HeLa cells. As this photosensitizer competed withcytochrome C in binding to COX, destruction of COX might not only disturb ATPsynthesis but could expedite the release of cytochrome C to the cytosolinducing apoptosis.