Calcineurin, Mitochondrial Membrane Potential, and Cardiomyocyte Apoptosis

Abstract

Mitochondria comprise ≈30% of the total intracellular volume within a mammalian cardiomyocyte.1 2 Not surprisingly, subtle alterations in mitochondrial function or membrane potential can have a dramatic influence on cardiomyocyte energy production and, ultimately, the health of an individual cell. Indeed, cellular injury or stress stimulation directly elicits alterations in mitochondrial architecture, membrane potential, and oxidative capacity, which are associated with an irreversible loss of mitochondrial matrix contents and integral membrane protein constituents such as cytochrome c oxidase.3 The release of cytochrome c and/or mitochondrial permeability transition directly mediates cellular apoptosis through calcium-sensitive proteases or through coupling proteins that coordinate the activation of caspases and DNA fragmentation enzymes.3 Given the high intracellular content of mitochondria in cardiomyocytes and the unabated requirement for high-energy phosphate carriers to maintain ionic gradients and active force generation, coordinated disturbances in mitochondrial function can dramatically affect cell survival. Recent investigation has suggested an emerging paradigm whereby stress-responsive intracellular signaling pathways directly and indirectly influence mitochondrial membrane potential, oxidative capacity, and the coupling of apoptosis initiating factors. For example, stress-responsive signaling through the c-Jun N-terminal kinases (JNKs) has been shown to initiate apoptosis in certain cell types by directly influencing proteins within the mitochondrial membranes.4 In addition, increased expression of the mitochondrial stabilizing Bcl proteins can be transcriptionally regulated through stress-responsive signaling pathways, which subsequently antagonize mitochondrial dysfunction and cytochrome c release.5 Activation of the intracellular kinase Akt also directly antagonizes mitochondrial-directed apoptosis by phosphorylating the mitochondrial destabilizing protein Bad, reducing cytochrome c release and caspase activation.6 Lastly, activation of nuclear factor-κB (NF-κB) signaling induces expression of stress-adaptive proteins such as Bcl-2, antioxidants, and calcium-regulating proteins.7 In general, signaling pathways such as the stress- and mitogen-activated protein kinases (SAPKs and MAPKs), protein kinase C (PKC), Akt, NF-κB, and the …