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Mitochondrial targets for cardioprotective therapeutics
doi:10.1016/j.freeradbiomed.2012.08.087 Symp. 3.2
Mitochondrial therapeutics in alcohol dependent hepatoxicity V.M. Darley Usmar* University of Alabama at Birmingham, USA Mitochondrial dysfunction is associated with a broad range of pathologies including diabetes, ethanol toxicity and cardiac failure. It is now becoming clear that the loss of mitochondrial function may be important in response to stress and signaling. In alcohol-dependent hepatotoxicity the mitochondria are subject to the dual stressors of hypoxia and nitric oxide formation. This prooxidant and pro-inflammatory environment has been associated with steatosis which suggests that mitochondrial dysfunction is intimately associated with the pathogenesis of steatosis. This concept was tested in vivo with an alcohol model of hepatotoxicity and the mitochondrial antioxidant Mito Q. The modification of proteins by lipid peroxidation products and reactive nitrogen species was inhibited by Mito Q and this was associated with a suppression of both hypoxia and steatosis. The autophagy-lysosomal pathway occurs in response to alcohol toxicity and MitoQ appears to enhance the processes leading to improved mitochondrial quality control. These data suggest that a key role of mitochondrially targeted antioxidants is to modulate the retrograde signaling pathways mediated by the interaction of reactive oxygen and nitrogen species with mitochondria.
amenable to high throughout screening approaches. We have used a readily available 24-well plate based respirometry apparatus, adapted for argon gas flow, to afford a plate based model of IR injury using H9c2 cardiomyocytes, with post-IR cell death as an end-point. Screening a library of 2000 small molecules led to identification of a number of agents that were validated for cardioprotection in a perfused heart model of IR injury. Several of the cardioprotective molecules acted by altering cardiac metabolism or triggering mitophagy (mitochondria specific autophagy), both of which are hallmarks of the endogenous protective pathway of ischemic preconditioning. In addition, the data set affords insight into the relationship between the effect of agents on ischemic protection and cellular bioenergetics. This and other screening efforts for mitochondrially targeted protective agents will be discussed. Keywords: Mitochondria, High-Throughout Screen, Ischemia, Metabolism doi:10.1016/j.freeradbiomed.2012.08.089 Symp. 3.4
Modulating the mitochondrial F0F1-ATPASE as a therapeutic strategy for systematic autoimmunity G.S. Glick, University of Michigan, USA
Mitochondrial targets for cardioprotective therapeutics
My lab has identified several families of pro-apoptotic small molecules that possess steroid-like efficacy in animal models of lupus, rheumatoid arthritis, psoriasis, graft-versus-host disease and colitis. These compounds differ from current immuno-modulators as they are not broadly toxic and are highly selective for pathogenic, disease-causing lymphocytes in preference to the normal immune cells that fight infection. These agents modulate a target that is central to the cellular bioenergetics machinery. In this lecture, I will discuss how differences in the bioenergetics of normal and pathogenic lymphocytes give rise to the observed selectivity and pharmacodynamics. Our findings challenge the current paradigm of lymphocyte bioenergetics, and suggest how metabolism-altering drugs hold promise as novel immunotherapeutics with improved safety and efficacy for a broad spectrum of diseases.
P.S. Brookes* University of Rochester Medical Center, USA
doi:10.1016/j.freeradbiomed.2012.08.090
Keywords: mitochondria, alcohol, hepatotoxicity, nitric oxide doi:10.1016/j.freeradbiomed.2012.08.088
Symp. 3.3
Cardiac ischemia-reperfusion (IR) injury is a significant a cause of morbidity and mortality in western societies, for which the current therapeutic options are limited. Traditionally, models of IR injury have not been
S10
Symposium 4: Insulin Resistance and RedoxModulated Signaling
Mitochondrial therapeutics in alcohol dependent hepatoxicity V.M. Darley Usmar* University of Alabama at Birmingham, USA Mitochondrial dysfunction is associated with a broad range of pathologies including diabetes, ethanol toxicity and cardiac failure. It is now becoming clear that the loss of mitochondrial function may be important in response to stress and signaling. In alcohol-dependent hepatotoxicity the mitochondria are subject to the dual stressors of hypoxia and nitric oxide formation. This prooxidant and pro-inflammatory environment has been associated with steatosis which suggests that mitochondrial dysfunction is intimately associated with the pathogenesis of steatosis. This concept was tested in vivo with an alcohol model of hepatotoxicity and the mitochondrial antioxidant Mito Q. The modification of proteins by lipid peroxidation products and reactive nitrogen species was inhibited by Mito Q and this was associated with a suppression of both hypoxia and steatosis. The autophagy-lysosomal pathway occurs in response to alcohol toxicity and MitoQ appears to enhance the processes leading to improved mitochondrial quality control. These data suggest that a key role of mitochondrially targeted antioxidants is to modulate the retrograde signaling pathways mediated by the interaction of reactive oxygen and nitrogen species with mitochondria.
amenable to high throughout screening approaches. We have used a readily available 24-well plate based respirometry apparatus, adapted for argon gas flow, to afford a plate based model of IR injury using H9c2 cardiomyocytes, with post-IR cell death as an end-point. Screening a library of 2000 small molecules led to identification of a number of agents that were validated for cardioprotection in a perfused heart model of IR injury. Several of the cardioprotective molecules acted by altering cardiac metabolism or triggering mitophagy (mitochondria specific autophagy), both of which are hallmarks of the endogenous protective pathway of ischemic preconditioning. In addition, the data set affords insight into the relationship between the effect of agents on ischemic protection and cellular bioenergetics. This and other screening efforts for mitochondrially targeted protective agents will be discussed. Keywords: Mitochondria, High-Throughout Screen, Ischemia, Metabolism doi:10.1016/j.freeradbiomed.2012.08.089 Symp. 3.4
Modulating the mitochondrial F0F1-ATPASE as a therapeutic strategy for systematic autoimmunity G.S. Glick, University of Michigan, USA
Mitochondrial targets for cardioprotective therapeutics
My lab has identified several families of pro-apoptotic small molecules that possess steroid-like efficacy in animal models of lupus, rheumatoid arthritis, psoriasis, graft-versus-host disease and colitis. These compounds differ from current immuno-modulators as they are not broadly toxic and are highly selective for pathogenic, disease-causing lymphocytes in preference to the normal immune cells that fight infection. These agents modulate a target that is central to the cellular bioenergetics machinery. In this lecture, I will discuss how differences in the bioenergetics of normal and pathogenic lymphocytes give rise to the observed selectivity and pharmacodynamics. Our findings challenge the current paradigm of lymphocyte bioenergetics, and suggest how metabolism-altering drugs hold promise as novel immunotherapeutics with improved safety and efficacy for a broad spectrum of diseases.
P.S. Brookes* University of Rochester Medical Center, USA
doi:10.1016/j.freeradbiomed.2012.08.090
Keywords: mitochondria, alcohol, hepatotoxicity, nitric oxide doi:10.1016/j.freeradbiomed.2012.08.088
Symp. 3.3
Cardiac ischemia-reperfusion (IR) injury is a significant a cause of morbidity and mortality in western societies, for which the current therapeutic options are limited. Traditionally, models of IR injury have not been
S10
Symposium 4: Insulin Resistance and RedoxModulated Signaling