Abstract
The survival of cardiomyocytes must be ensured as the myocardium adjusts to a myriad of competing physiological and pathophysiological demands. A significant loss of these contractile cells, together with their replacement by stiff fibrillar collagen in the form of fibrous tissue accounts for a transition from a usually efficient muscular pump into one that is failing. Cellular and subcellular mechanisms involved in the pathogenic origins of cardiomyocyte cell death have long been of interest. This includes programmed molecular pathways to either necrosis or apoptosis, which are initiated from ischemic or nonischemic origins. Herein, we focus on the central role played by a mitochondriocentric signal-transducer-effector pathway to nonischemic cardiomyocyte necrosis, which is common to acute and chronic stressor states. We begin by building upon the hypothesis advanced by Albrecht Fleckenstein and coworkers some 40 years ago based on the importance of calcitropic hormone-mediated intracellular Ca2+ overloading, which predominantly involves subsarcolemmal mitochondria and is the signal to pathway activation. Other pathway components, which came to be recognized in subsequent years, include the induction of oxidative stress and opening of the mitochondrial inner membrane permeability transition pore. The ensuing loss of cardiomyocytes and consequent replacement fibrosis, or scarring, represents a disease of adaptation and a classic example of when homeostasis begets dyshomeostasis.
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This work was supported, in part, by NIH grants R01-HL73043 and R01-HL90867 (KTW). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Authors have no conflicts of interest to disclose. We wish to express our deep gratitude to Richard A. Parkinson, MEd, for editorial assistance and illustrations.
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This article is published as part of the special issue on “Cell-specific roles of mitochondrial Ca2+ handling.”
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Khan, M.U., Cheema, Y., Shahbaz, A.U. et al. Mitochondria play a central role in nonischemic cardiomyocyte necrosis: common to acute and chronic stressor states. Pflugers Arch - Eur J Physiol 464, 123–131 (2012). https://doi.org/10.1007/s00424-012-1079-x
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DOI: https://doi.org/10.1007/s00424-012-1079-x