MATTHEW PICKLO, Ph.D.
Dr. Picklo is a Delaware native and earned his bachelors degree in Biological Sciences from the University of Delaware in 1990. He obtained his Ph.D. in Pharmacology from Vanderbilt University in 1995. Dr. Picklo was a research fellow at University College London from 1995-1996. From 1996-2001, he was a research fellow in the Division of Neuropathology at Vanderbilt University where he studied the role of mitochondrial dysfunction in neurodegenerative disease. In 2001, Dr. Picklo began as an assistant professor in the Department of Pharmacology, Physiology, and Therapeutics at the University of North Dakota and was promoted and tenured in 2007. In 2008, he was awarded the Hermann Esterbauer Award for his extensive work into the biochemistry of lipid peroxidation. In 2009, Dr. Picklo moved to the position of Research Leader at the GFHNRC.
Dr. Picklo research interests focus upon the role of oxidative damage and anti-oxidants in health and disease. Dr. Picklo's research ranges from the molecular level to the clinical level.
Dr. Picklo research team has two main research interests:
(1) Reactive oxygen species (ROS) are common by-products of everyday normal cellular function. Several studies indicate that excessive generation of ROS leads to disease. However, recent data show that non-pathological levels of ROS are necessary for positive adaptations to exercise.
The effects of insulin are regulated by ROS. Under normal conditions, ROS are necessary for increasing the potency of insulin as a result of exercise. On the other hand, ROS are implicated in causing insulin resistance as a result of obesity. How is it that ROS have both good and bad effects? How does supplementation with anti-oxidants influence the "good" and "bad" effects of ROS? Dr. Picklo's research team studies these questions using transgenic mouse models, nutrient and exercise paradigms, and studies in human volunteers.
(2) Oxidative damage to n-6 and n-3 polyunsaturated fatty acids leads to the generation of multiple cytotoxic aldehydes. Dr. Picklo has studied the mechanisms of toxicity and the ways that cells detoxify these aldehydes. Do levels of these cytotoxic aldehydes increase in obesity? How do cells adapt to aldehydes in the context of obesity? These questions are being answered using in vitro and in vivo models.
Discovered cell-specific expression of aldehyde dehydrogenases and aldo-keto reductases. Dr. Picklo's research addressed the disposition of lipid peroxidation products, particularly the n-6 lipid-aldehyde product trans-4-hydroxy-2-nonenal (HNE), and their role in mitochondrial dysfunction. His underlying hypothesis is that the detoxification of aldehydes is impaired in chronic CNS disease. In studying the localization and activities of aldehyde metabolizing enzymes in sections of the human brain, Dr. Picklo was the first to recognize that the aldehyde dehydrogenases and aldo-keto reductases have cell-specific expression. This work showed mitochondrial class 2 aldehyde dehydrogenase (ALDH2) to be exclusively expressed in astrocytes and microglia in the human cerebral cortex, and expression and activity of this enzyme elevated in Alzheimer's disease.
Discovered that mitochondria play a major role in detoxifying lipid-aldehydes in brain, and that this is accomplished by the GABA metabolizing enzyme, ALDH5A. Dr. Picklo's work was the first to demonstrate in a live CNS model (rat) that the mitochondrion is the major site of HNE metabolism. He followed up this discovery by showing that the enzyme ALDH5A (an essential component for neurotransmitter metabolism) is the major oxidase for HNE; he did this in a unique model (rat brain mitochondria and recombinantly expressed enzymes) he developed for that purpose.
Discovered that the metabolism of HNE is an enantioselective process. HNE is a racemic molecule in which the R-HNE and S-HNE enantiomers have different reactivity with target molecules, with the S-HNE enantiomer being more toxic in many different models. Dr. Picklo developed a novel derivatization method for facile, HPLC separation of the R- and S-enantiomers and HNE and its metabolites. His group was thus able to discover the molecular basis for the apparent differences in toxicity, that HNE metabolism is enantioselective (R-HNE > S-HNE). They demonstrated this in freshly isolated brain mitochondria, showing enantioselectivity due to differential oxidation of HNE by ALDHs.
Elucidated the roles of mitochondrial energy status, Mg2+ and aldehyde dehydrogenase isoforms in lipid-aldehyde metabolism. Dr. Picklo advanced results from previous studies by demonstrating that mitochondrial redox balance, through the TCA cycle and complex I activity, is a potent biological switch for regulating aldehyde detoxification. For this work he developed new HPLC-UV and LC-MS/MS methods to determine HNE metabolites in freshly isolated rat brain mitochondria. He used this analytical approach plus recombinant enzymes, to demonstrate that the enzyme ALDH5A in rat brain mitochondria confers enantioselectivity to HNE metabolism, and that physiologic levels of Mg2+ stimulate HNE oxidation by ALDH2 and alter the enantioselectivity of the latter enzyme.