The Journal of Experimental Medicine
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Published online 2 October 2000.
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© The Rockefeller University Press, 0022-1007/2000/10/1001/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 7, October 2, 2000 1001-1014

Original Article

Reactive Oxygen Species (Ros-Induced) Ros Release: A New Phenomenon Accompanying Induction of the Mitochondrial Permeability Transition in Cardiac Myocytes



Dmitry B. Zorova,d, Charles R. Filburnb, Lars-Oliver Klotzb, Jay L. Zweierc, and Steven J. Sollotta

a Laboratory of Cardiovascular Sciences, Gerontology Research Center, Intramural Research Program, National Institute on Aging, National Institutes of Health,
b Laboratory of Biological Chemistry, Gerontology Research Center, Intramural Research Program, National Institute on Aging, National Institutes of Health,
c Department of Medicine, Division of Cardiology and the Electron Paramagnetic Resonance Center, Johns Hopkins Medical Institutions, Baltimore, Maryland 21224
d Department of Bioenergetics, A.N. Belozersky Institute of Physico-Chemical Biology, Moscow 119899, Russia
Laboratory of Cardiovascular Science, Intramural Research Program, Gerontology Research Center, Box 13, National Institute on Aging, 5600 Nathan Shock Dr., Baltimore, MD 21224-6825.410-558-8150410-558-8657

We sought to understand the relationship between reactive oxygen species (ROS) and the mitochondrial permeability transition (MPT) in cardiac myocytes based on the observation of increased ROS production at sites of spontaneously deenergized mitochondria. We devised a new model enabling incremental ROS accumulation in individual mitochondria in isolated cardiac myocytes via photoactivation of tetramethylrhodamine derivatives, which also served to report the mitochondrial transmembrane potential, {Delta}{Psi}. This ROS accumulation reproducibly triggered abrupt (and sometimes reversible) mitochondrial depolarization. This phenomenon was ascribed to MPT induction because (a) bongkrekic acid prevented it and (b) mitochondria became permeable for calcein (~620 daltons) concurrently with depolarization. These photodynamically produced "triggering" ROS caused the MPT induction, as the ROS scavenger Trolox prevented it. The time required for triggering ROS to induce the MPT was dependent on intrinsic cellular ROS-scavenging redox mechanisms, particularly glutathione. MPT induction caused by triggering ROS coincided with a burst of mitochondrial ROS generation, as measured by dichlorofluorescein fluorescence, which we have termed mitochondrial "ROS-induced ROS release" (RIRR). This MPT induction/RIRR phenomenon in cardiac myocytes often occurred synchronously and reversibly among long chains of adjacent mitochondria demonstrating apparent cooperativity. The observed link between MPT and RIRR could be a fundamental phenomenon in mitochondrial and cell biology.

Key Words: mitochondria • redox • heart • nitric oxide • Ca2+ sparks

Abbreviations used in this paper: BA, bongkrekic acid; EPR, electron paramagnetic resonance; ETC, electron transport chain; MPT, mitochondrial permeability transition; RIRR, ROS-induced ROS release; ROS, reactive oxygen species.

© 2000 The Rockefeller University Press


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