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
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.
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.
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
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
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.