Mitochondria in Coronary Reperfusion Injury and Cancer: c subunit of FoF1-ATP synthase and Mcl-1 as potential therapeutic targets.

Mitochondria are able to decode a variety of extracellular stimuli into greatly different intracellular actions, ranging from energy production to cell death. When mitochondrial Ca2+ homeostasis is compromised, very different pathological conditions can occur, from cancer to ischemia/reperfusion injury, depending on the cell type and pathway involved. During my Phd I tried to shed light on both mechanisms by which mitochondria are responsible for sensitizing cancer cells to Ca2+dependent apoptotic stimuli in HeLa cells and how they can influence cell death and infarct size (IS) in a STEMI-patients cohort. In the first case, performed experiments by using splice-switching antisense oligonucleotides (ASOs) specific for Mcl-1, allowed to increase the synthesis of Mcl-1S which induced a concurrent reduction of Mcl-1L, resulting in increased sensitivity of cancer cells to apoptotic stimuli. The Mcl-1 ASOs also induced mitochondrial hyperpolarization and a consequent increase in mitochondrial Ca2+ accumulation. The high Mcl-1S/L ratio correlated with significant hyperfusion of the entire mitochondrial network, which occurred in a dynamin-related protein (Drp1)–dependent manner. I propose that the Mcl-1L/S balance is a novel regulatory factor controlling the mitochondrial fusion and fission machinery. In the second part, the ongoing study on c subunit of FoF1-ATP synthase (Csub) in biological samples from STEMI patients showed that circulating Csub was strongly related to infarct size, ST-segment resolution and clinical outcome. Moreover, Csub expression found in fibroblasts from skin biopsy had a good correlation with mPTP activity values and myocardial salvage index (MSI) belonging to the same STEMI-patients.