© 2001 American Heart Association, Inc.
Editorials |
Mitochondria
Gateway for Cytoprotection
From the Division of Cardiovascular Diseases, Departments of Medicine, Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Mayo Foundation, Rochester, Minn.
Correspondence to Andre Terzic, Guggenheim 7, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail terzic.andre@mayo.edu
Key Words: cardioprotection • energetics • metabolic signaling • potassium channel openers • heart
Tissues with high-energy turnover, such as heart muscle, heavily depend on ATP produced by mitochondrial oxidative phosphorylation, and therefore display particular vulnerability to insults induced by deprivation of oxygen and/or metabolic substrates.1,2 Along with oxidative phosphorylation, mitochondria are central in regulating Ca2+ signaling, free radical production, and release of apoptosis-inducing factors.3–7 Through dynamic feedback communication, mitochondrial functions are tightly integrated with cellular processes securing ionic and energetic homeostasis.2,8 In particular, phosphotransfer relays have emerged as mechanisms responsible for efficient coupling of mitochondrial ATP production with cellular sites of ATP utilization and/or ATP sensing.9–12 In this way, mitochondria can orchestrate vital processes throughout the cell, ultimately supporting cellular life and determining cell longevity.4,6,13 In fact, mitochondrial dysfunction disrupts cellular energy metabolism precipitating progression of degenerative disease states.13,14 Thus, preservation of mitochondria and associated energetic pathways has paramount significance in the ability of cardiomyocytes to withstand metabolic injury. Yet, little is known about mechanisms that would enhance mitochondrial tolerance to stress and induce cellular protection.
Recently, it has become apparent that mitochondria harbor sufficient functional plasticity to respond to metabolic challenge.15 By virtue of their ability to generate and accommodate stress-induced signals, mitochondria could serve as triggers and/or end-effectors in the cycle of events protecting mitochondrial integrity, transfer, and utilization of ATP and ultimately cell survival.2,7,13–17 Such new developments in our understanding of mitochondrial biology provide an exciting opportunity in enhancing cellular tolerance to stress by exploiting mitochondria-mediated cytoprotection.17
Several strategies that directly modulate mitochondrial respiration, ATP production, ion transport, cytochrome c
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