Modulation of Mitochondrial Function by Pro-Oxidants
Principal Investigator: LUKE IGNATIUS SZWEDA
Abstract: Complications arising from reduction of blood supply to the heart are a leading cause of death and debilitation worldwide. Nevertheless, restoration of coronary blood flow to seemingly viable myocardial tissue is often accompanied by loss of cardiac function and, in the long term, development of heart failure. This paradoxical phenomenon, broadly termed ischemia/reperfusion injury, is manifested more severely in the elderly. Mitochondria likely play a central role in myocardial ischemia/reperfusion injury. Critical for the maintenance of cardiac energy status and function, mitochondria exhibit declines in the rate of respiration and oxidative phosphorylation during ischemia, with further age-dependent deficits evident upon reperfusion. The proposed studies seek to define mechanisms responsible for this loss in function by unifying two events associated with ischemia/reperfusion: Ca2+ overload and pro-oxidant production. Cardiac ischemia results in detachment of cytochrome c from the inner mitochondrial membrane, an event responsible for declines in the rate of electron transport. During reperfusion, the redox sensitive enzymes complex I, a-ketoglutarate dehydrogenase, and aconitase exhibit declines in activity. Exposure of isolated mitochondria to alterations in pH and Ca2+ concentration that mimic the transition from ischemia to reperfusion results in cytochrome c dissociation and oxidative inhibition of these redox sensitive enzymes. Depending on the magnitude and duration of oxidative stress, reversible inhibition can progress to irreversible inactivation. It is hypothesized that: Increases in mitochondrial Ca2+ concentration during myocardial ischemia/reperfusion lead to dissociation of cytochrome c from the inner mitochondrial membrane resulting in an increase in free radical production and oxidative inhibition of redox sensitive enzymes. This transiently reduces the rates of mitochondrial respiration, free radical production, and susceptibility to irreversible oxidative damage. Aging augments mitochondrial Ca2+ overload, increasing the likelihood of progression from reversible modulation to irreversible inactivation of mitochondrial function. Utilizing an in vivo rat model, durations of cardiac ischemia and reperfusion will be varied using animals of different ages to identify molecular events that result in increased mitochondrial pro-oxidant production (Aim 1), specific targets and mechanisms of redox- dependent modification (Aim 2), biochemical consequences of oxidative modification (Aim 2), and age- dependent factors that promote irreparable loss in mitochondrial function during cardiac ischemia/reperfusion (Aims 1 and 2). Elucidation of molecular events responsible for ischemia/reperfusion injury is required for optimization of strategies for favorably influencing the outcome particularly in the elderly population. Lay Description: Heart disease is a leading cause of debilitation and death, particularly in the aging population. Our studies seek to define age-related factors that enhance the severity of heart disease in an effort to design strategies to improve the outcome.
Funding Period: ----------------1999 - ---------------2011-
more information: NIH RePORT
- Preconditioning prevents loss in mitochondrial function and release of cytochrome c during prolonged cardiac ischemia/reperfusionKathleen C Lundberg
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH, USA
Arch Biochem Biophys 453:130-4. 2006....
- Reversible inhibition of alpha-ketoglutarate dehydrogenase by hydrogen peroxide: glutathionylation and protection of lipoic acidMilana A B Applegate
Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA
Biochemistry 47:473-8. 2008..Glutathionylation of alpha-ketoglutarate dehydrogenase can therefore be viewed as an antioxidant response protecting the enzyme from oxidative damage...
- A quantitative proteomic profile of the Nrf2-mediated antioxidant response of macrophages to oxidized LDL determined by multiplexed selected reaction monitoringCaroline S Kinter
Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America
PLoS ONE 7:e50016. 2012..All of the oxLDL-mediated increases were attenuated by Nrf2 siRNA. These results reveal a specific, multifaceted response of the foam cells to the incoming toxic oxidized LDL...
- High dietary fat selectively increases catalase expression within cardiac mitochondriaPaul M Rindler
Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
J Biol Chem 288:1979-90. 2013....
- Glutathionylation of α-ketoglutarate dehydrogenase: the chemical nature and relative susceptibility of the cofactor lipoic acid to modificationAaron L McLain
Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA Department of Biochemistry and Molecular Biology, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA
Free Radic Biol Med 61:161-9. 2013..These findings offer chemical information necessary for the identification of mechanisms and physiological implications of KGDH glutathionylation. ..
- Rapid inhibition of pyruvate dehydrogenase: an initiating event in high dietary fat-induced loss of metabolic flexibility in the heartClair Crewe
Free Radical Biology and Aging Research Program Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America Department of Biochemistry and Molecular Biology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States of America
PLoS ONE 8:e77280. 2013..Thus, our data indicate that diet-induced inhibition of pyruvate dehydrogenase may be an initiating event in decreased oxidation of glucose and increased reliance of the heart on fatty acids for energy production. ..
- Mitochondrial superoxide production and respiratory activity: biphasic response to ischemic durationSatoshi Matsuzaki
Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, 825 N E 13th Street, Oklahoma City, OK 73104, USA
Arch Biochem Biophys 484:87-93. 2009..In contrast, longer ischemic durations were accompanied by a decrease in NADH oxidase activity, reflected by deficits in complexes I and IV activities...
- Regulated production of free radicals by the mitochondrial electron transport chain: Cardiac ischemic preconditioningSatoshi Matsuzaki
Free Radical Biology and Aging Program, Oklahoma Medical Research Foundation, Oklahoma City, 73104, United States
Adv Drug Deliv Rev 61:1324-31. 2009..The aim of this review is to present and discuss evidence for the regulated production of superoxide by the electron transport chain within the ischemic preconditioning paradigm of redox regulation...
- α-Ketoglutarate dehydrogenase: a mitochondrial redox sensorAaron L McLain
Free Radical Biology and Aging Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA
Free Radic Res 45:29-36. 2011..KGDH is therefore a likely redox sensor, reversibly altering metabolism to reduce oxidative damage and, under severe oxidative stress, acting as a sentinel of mitochondrial viability...