doi: 10.1161/hh1201.093159
© 2001 American Heart Association, Inc.
Editorial |
Calcineurin, Mitochondrial Membrane Potential, and Cardiomyocyte Apoptosis
From the Department of Pediatrics, University of Cincinnati, Children’s Hospital Medical Center, Division of Molecular Cardiovascular Biology, Cincinnati, Ohio.
Correspondence to Jeffery D. Molkentin, PhD, Children’s Hospital Medical Center, Division of Molecular Cardiovascular Biology, 3333 Burnet Ave, Cincinnati, OH 45229-3039. E-mail jeff.molkentin@chmcc.org
Key Words: apoptosis • heart • calcineurin • mitochondria • ischemia
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
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