Steven J. Sollott, MD, Chief
Environmental stresses converge on the mitochondria that can trigger or inhibit cell death. Excitable, post-mitotic cells (such as cardiac myocytes in heart, and neurons in brain), in response to sub-lethal noxious stress engage mechanisms affording protection from subsequent insults. These protection mechanisms involve activation of endogenous signaling which can confer significant resistance to oxidant and other stresses associated with hypoxia/reoxygenation (i.e., during a heart attack or stroke), which promotes the enhanced capacity for cell survival. One of our main goals is to understand the nature and control of mitochondrial instability and cell death during oxidant and other harmful environmental stresses, and the signaling pathways necessary to engage specific intrinsic mechanisms of protection of cardiac myocytes and neurons during ischemic injury. The long-term objectives are to obtain insights critical for the development of novel therapies to limit the damage from heart attack and stroke, helping to reduce the clinical burden of these diseases. We are examining the hypothesis that the sensitivity of the mitochondrial permeability transition pore to oxidant stress can serve as a biomarker of mitochondrial fitness during aging. Failure to supply energy to match the body's demands limits the functional reserve capacity, and under certain periods of stress, such as ischemia, can lead to irreversible cell and tissue damage. This matching is critical in tissues with high and rapidly fluctuating metabolic rates such as the heart. Mitochondria are the main ATP suppliers to meet cellular demands. Our second major aim is to examine the bioenergetic mechanisms responsible for matching ATP supply and demand. Identification of the matching mechanisms between ATP demand and supply could allow development of agents with better specificity that could potentially lead to the discovery of effective treatments, for example, for pathologies involving a failure of energy supply/demand matching, such as occurs in heart failure which afflicts millions of persons worldwide.
- Control of mitochondrial fitness and damage.
- Control Mechanisms for Matching ATP Supply and Demand in Heart Mitochondria.
Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Zorov DB, Juhaszova M, Sollott SJ. Physiol Rev. 2014 Jul;94(3):909-50
Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore. Juhaszova M, Zorov DB, Kim SH, Pepe S, Fu Q, Fishbein KW, Ziman BD, Wang S, Ytrehus K, Antos CL, Olson EN, Sollott SJ. J Clin Invest. 2004 Jun;113(11):1535-49
Endogenous nitric oxide mechanisms mediate the stretch dependence of Ca2+ release in cardiomyocytes. Petroff MG, Kim SH, Pepe S, Dessy C, Marbán E, Balligand JL, Sollott SJ. Nat Cell Biol. 2001 Oct;3(10):867-73.
Paclitaxel stent coating inhibits neointimal hyperplasia at 4 weeks in a porcine model of coronary restenosis. Heldman AW, Cheng L, Jenkins GM, Heller PF, Kim DW, Ware M Jr, Nater C, Hruban RH, Rezai B, Abella BS, Bunge KE, Kinsella JL, Sollott SJ, Lakatta EG, Brinker JA, Hunter WL, Froehlich JP. Circulation. 2001 May 8;103(18):2289-95.
Reactive oxygen species (ROS)-induced ROS release: a new phenomenon accompanying induction of the mitochondrial permeability transition in cardiac myocytes. Zorov DB, Filburn CR, Klotz LO, Zweier JL, Sollott SJ. J Exp Med. 2000 Oct 2;192(7):1001-14.