department of pharmacology

Charles Hoppel, M.D.

Hoppel

Professor of Pharmacology and Medicine
Chief of Clinical Pharmacology
Director of the Center for Mitochondrial Diseases
Division of Clinical Phamacology

Phone: (216) 368-3147
Fax: 216-368-1300
E-mail: charles.hoppel@case.edu
W147 Wood Building

Research

The main focus of the laboratory is mitochondrial fatty acid oxidation. The organization of the pathway for mitochondrial fatty acid oxidation is of particular interest as a potential site for control of the system. Mitochondrial contact sites contain the protein translocases for protein translocation into the mitochondria and the peripheral benzodiazepine receptor. We have data that support the localization of key enzymes, such as the long-chain acyl-CoA synthetase and carnitine palmitoyltransferase of fatty acid oxidation to these contact sites. We have proposed a fatty acid/carnitine shuttle through the contact sites. The characterization of this shuttle coupled with the determination of its localization within the mitochondria will be essential steps

During ischemia/reperfusion in the elderly heart there is increased myocardial damage compared to adult controls. There is a decrease in the sensitivity of carnitine palmitoyl-transferase-I to a competitive inhibitor, malonyl-CoA, without a change in the total activity under this experimental protocol. We have investigated the mitochondrial changes that occur during ischemia in the elderly rat heart. There is a decrease in the activity of complex III, ubiquinone-cytochrome c oxidoreductase, only in the interfibrillar mitochondria in the elderly heart and the activity does not change in those mitochondria located underneath the sarcolemmal membrane (subsarcolemmal mitochondria). The defect in the interfibrillar mitochondria involves the binding of cytochrome c to complex III and is not due to a decrease in the catalytic subunits. We are proposing to determine the molecular mechanisms underlining the oxidative damage to complex III and to the enzymes of fatty acid oxidation. We have recently purchased an electrospray mass spectrometer and currently are examining the determination of peptides following oxidative damage using the mass spectrometer.

Selected References:

McComsey GA, Paulsen DM, Lonergan JT, Hessenthaler SM, Hoppel CL , Williams VC, Fisher RL, Cherry CL, White-Owen C, Thompson KA, Ross ST, Hernandez JE, Ross LL. Improvements in lipoatrophy, mitochondrial DNA levels and fat apoptosis after replacing stavudine with abacavir or zidovudine. AIDS . 2005 19(1):15-23.

Bian F, Kasumov T, Thomas KR, Jobbins KA, David F, Minkler PE, Hoppel CL , Brunengraber H. Peroxisomal and mitochondrial oxidation of fatty acids in the heart, assessed from the 13 C-labeling of malonyl-CoA and the acetyl moiety of citrate. J Biol Chem. 2004 Dec 16; [Epub ahead of print]

Cooney MM, Tserng KY, Makar V, McPeak RJ, Ingalls ST, Dowlati A, Overmoyer B, McCrae K, Ksenich P, Lavertu P, Ivy P, Hoppel CL , Remick S. A phase IB clinical and pharmacokinetic study of the angiogenesis inhibitor SU5416 and paclitaxel in recurrent or metastatic carcinoma of the head and neck. Cancer Chemother Pharmacol. 2005 55(3):295-300

Cooper BW, Veal GJ, Radivoyevitch T, Tilby MJ, Meyerson HJ, Lazarus HM, Koc ON, Creger RJ, Pearson G, Nowell GM, Gosky D, Ingalls ST, Hoppel CL , Gerson SL. A phase I and pharmacodynamic study of fludarabine, carboplatin, and topotecan in patients with relapsed, refractory, or high-risk acute leukemia. Clin Cancer Res. 2004 10(20):6830-9.

Steiber A, Kerner J, Hoppel CL . Carnitine: a nutritional, biosynthetic, and functional perspective. Mol Aspects Med. 2004 25(5-6):455-73.

Lesnefsky EJ, Chen Q, Moghaddas S, Hassan MO, Tandler B, Hoppel CL . Blockade of electron transport during ischemia protects cardiac mitochondria. J Biol Chem. 2004 279(46):47961-7.

Kayser EB, Sedensky MM, Morgan PG, Hoppel CL . Mitochondrial oxidative phosphorylation is defective in the long-lived mutant clk-1. J Biol Chem. 2004 279 (52):54479-86.

Kerner J, Distler AM, Minkler P, Parland W, Peterman SM, Hoppel CL . Phosphorylation of rat liver mitochondrial carnitine palmitoyltransferase-I: effect on the kinetic properties of the enzyme. J Biol Chem. 2004 279(39):41104-13

Chandler MP, Kerner J, Huang H, Vazquez E, Reszko A, Martini WZ, Hoppel CL , Imai M, Rastogi S, Sabbah HN, Stanley WC. Moderate severity heart failure does not involve a downregulation of myocardial fatty acid oxidation. Am J Physiol Heart Circ Physiol. 2004 287(4):H1538-43.

Restivo NL, Srivastava MD, Schafer IA, Hoppel CL . Mitochondrial dysfunction in a patient with Crohn's disease: possible role in pathogenesis. J Pediatr Gastroenterol Nutr. 2004 38(5):534-8

Lesnefsky EJ, Chen Q, Slabe TJ, Stoll MS, Minkler PE, Hassan MO, Tandler B, Hoppel CL . Ischemia, rather than reperfusion, inhibits respiration through cytochrome oxidase in the isolated, perfused rabbit heart: role of cardiolipin. Am J Physiol Heart Circ Physiol. 2004 287(1):H258-67

Reszko AE, Kasumov T, David F, Jobbins KA, Thomas KR, Hoppel CL , Brunengraber H, Des Rosiers C. Peroxisomal fatty acid oxidation is a substantial source of the acetyl moiety of malonyl-CoA in rat heart. J Biol Chem. 2004 279(19):19574-9

Lesnefsky EJ, Hoppel CL . Ischemia-reperfusion injury in the aged heart: role of mitochondria. Arch Biochem Biophys. 2003 420(2):287-97

Chen Q, Vazquez EJ, Moghaddas S, Hoppel CL , Lesnefsky EJ. Production of reactive oxygen species by mitochondria: central role of complex III. J Biol Chem. 2003 278(38):36027-31

Reszko AE, Kasumov T, Pierce BA, David F, Hoppel CL , Stanley WC, Des Rosiers C, Brunengraber H. Assessing the reversibility of the anapleurotic reactions of the propionyl-CoA pathway in heart and liver. J Biol Chem. 2003 278(37):34959-65

Konstan MW, Krenicky JE, Finney MR, Kirchner HL, Hilliard KA, Hilliard JB, Davis PB, Hoppel CL . Effect of ibuprofen on neutrophil migration in vivo in cystic fibrosis and healthy subjects. J Pharmacol Exp Ther. 2003 306(3):1086-9120:

Moghaddas S, Hoppel CL , Lesnefsky EJ. Aging defect at the QO site of complex III augments oxyradical production in rat heart interfibrillar mitochondria. Arch Biochem Biophys. 2003 414(1):59-66.