Gary M Fiskum

Publication Detail

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Pyruvate dehydrogenase complex: metabolic link to ischemic brain injury and target of oxidative stress.

Erica Martin; Robert E Rosenthal; Gary Fiskum (Profiled Authors: Gary M Fiskum; Robert E Rosenthal)

Department of Anesthesiology, University of Maryland School of Medicine, 684 W. Baltimore Street, Baltimore, MD 21201, USA.
Journal of neuroscience research 2005;79(1-2):240-7.

The mammalian pyruvate dehydrogenase complex (PDHC) is a mitochondrial matrix enzyme complex (greater than 7 million Daltons) that catalyzes the oxidative decarboxylation of pyruvate to form acetyl CoA, nicotinamide adenine dinucleotide (the reduced form, NADH), and CO(2). This reaction constitutes the bridge between anaerobic and aerobic cerebral energy metabolism. PDHC enzyme activity and immunoreactivity are lost in selectively vulnerable neurons after cerebral ischemia and reperfusion. Evidence from experiments carried out in vitro suggests that reperfusion-dependent loss of activity is caused by oxidative protein modifications. Impaired enzyme activity may explain the reduced cerebral glucose and oxygen consumption that occurs after cerebral ischemia. This hypothesis is supported by the hyperoxidation of mitochondrial electron transport chain components and NAD(H) that occurs during reperfusion, indicating that NADH production, rather than utilization, is rate limiting. Additional support comes from the findings that immediate postischemic administration of acetyl-L-carnitine both reduces brain lactate/pyruvate ratios and improves neurologic outcome after cardiac arrest in animals. As acetyl-L-carnitine is converted to acetyl CoA, the product of the PDHC reaction, it follows that impaired production of NADH is due to reduced activity of either PDHC or one or more steps in glycolysis. Impaired cerebral energy metabolism and PDHC activity are associated also with neurodegenerative disorders including Alzheimer's disease and Wernicke-Korsakoff syndrome, suggesting that this enzyme is an important link in the pathophysiology of both acute brain injury and chronic neurodegeneration.

4 Originating Grant

• 1.

  Fiskum, Gary M

  NOVEL MECHANISMS OF MITOCHONDRIAL FREE RADIAL GENERATION

  11 March 2002 - 30 November 2004

  NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

• 2.

  Zielke, H Ronald

  Metabolic & Developmental Aspects of Mental Retardation

  1 May 1997 - 31 January 2009

  NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

• 3.

  MCKENNA, MARY C

  Metabolic &Developmental Aspects of Intellectual Disability

  1 May 1997 - 31 January 2014

  EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT

• 4.

  Fiskum, Gary

  Molecular Mechanisms of Ischemia Reperfusion Brain Injury

  1 May 1995 - 31 December 2008

  NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

Scientific Context

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