Mitochondria not only play a fundamental role in heart physiology but are also key effectors of dysfunction and death. This dual role assumes a new meaning after recent advances on the nature and regulation of the permeability transition pore, an inner membrane channel whose opening requires matrix Ca 2+ and is modulated by many effectors including reactive oxygen species, matrix cyclophilin D, Pi (inorganic phosphate), and matrix pH. The recent demonstration that the F-ATP synthase can reversibly undergo a Ca 2+ -dependent transition to form a channel that mediates the permeability transition opens new perspectives to the field. These findings demand a reassessment of the modifications of F-ATP synthase that take place in the heart under pathological conditions and of their potential role in determining the transition of F-ATP synthase from and energy-conserving into an energy-dissipating device.