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.
ATP Synthase K+- and H+-fluxes Drive ATP Synthesis and Enable Mitochondrial K+-“Uniporter” Function: II. Ion and ATP Synthase Flux Regulation. Juhaszova M, Kobrinsky E, Zorov DB, Nuss HB, Yaniv Y, Fishbein KW, de Cabo R, Montoliu L, Gabelli SB, Aon MA, Cortassa S, Sollott SJ. Function (Oxf). 2022 Jan 27;3(2):zqac001.
ATP Synthase K+- and H+-Fluxes Drive ATP Synthesis and Enable Mitochondrial K+-“Uniporter” Function: I. Characterization of Ion Fluxes. Juhaszova M, Kobrinsky E, Zorov DB, Nuss HB, Yaniv Y, Fishbein KW, de Cabo R, Montoliu L, Gabelli SB, Aon MA, Cortassa S, Sollott SJ. Function (Oxf). 2021 Dec 13;3(2):zqab065.
Mitochondrial health is enhanced in rats with higher vs. lower intrinsic exercise capacity and extended lifespan. Aon MA, Cortassa S, Juhaszova M, González-Reyes JA, Calvo-Rubio M, Villalba JM, Lachance AD, Ziman BD, Mitchell SJ, Murt KN, Axsom JEC, Alfaras I, Britton SL, Koch LG, de Cabo R, Lakatta EG, Sollott SJ. NPJ Aging Mech Dis. 2021 Jan 4;7(1):1.
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.
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.