The adult parasitic helminths presents a unique chemotherapeutic problem. Unlike other pathogens, in which metabolic events associated with proliferation can be disrupted, the helminths are more sensitive to agents that alter energetic or energy-related events, neurotransmission or neuromuscular activity. Thus, as part of a three-pronged chemotherapeutic strategy, it is essential to understand and evaluate the energetic mechanisms of the helminths because such evaluations assist in the determination of vulnerable sites for specific chemotherapeutic attack and present a reasonable approach to the development and assay of agents displaying chemotherapeutic efficacy. The proposed research focuses on the energetic impact of two mitochondrial systems, i.e., the inner membrane-associated NADPH:NAD and NADH:NAD transhydrogenations, on the helminths and an evaluation of the key mitochondrial electron transport complex of the helminths employing adult H. diminuta as the model. A vast number of the adult helminths are predominantly anaerobic energetically and accumulate succinate (or products derived from succinate) as the result of carbohydrate catabolism. Succinate is formed by the essential, anaerobic, mitochondrial electron transport mechanism of the helminths. The studies proposed address the energetic significance of the transhydrogenations and characteristics of the mitochondrial complex associated with anaerobic energy generation. The proposed studies will permit a novel evaluation of the NAPDH:NAD system in terms of protonmotive function, transmembrane configuration, potential energy conservation and composition, the potential of the NADH:NAD system to act in vectorial transmembrane hydride translocation, and the possible association of the transhydrogenations with a """"""""Complex I"""""""" of helminth mitochondria.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI015597-07A2
Application #
3126254
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Project Start
1979-01-01
Project End
1990-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
7
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Bowling Green State University
Department
Type
Schools of Arts and Sciences
DUNS #
617407325
City
Bowling Green
State
OH
Country
United States
Zip Code
43403
Holowiecki, Andrew; Fioravanti, Carmen F (2015) NADH?NAD? Transhydrogenation in Adult Ascaris suum Mitochondria. J Parasitol 101:358-63
Vandock, Kurt P; Mitchell, Martin J; Fioravanti, Carmen F (2012) Effects of plant flavonoids on Manduca sexta (tobacco hornworm) fifth larval instar midgut and fat body mitochondrial transhydrogenase. Arch Insect Biochem Physiol 80:15-25
Fioravanti, C F; Vandock, K P (2010) Transhydrogenase and the anaerobic mitochondrial metabolism of adult Hymenolepis diminuta. Parasitology 137:395-410
Vandock, Kurt P; Drummond, Christopher A; Smith, Stan L et al. (2010) Midgut and fatbody mitochondrial transhydrogenase activities during larval-pupal development of the tobacco hornworm, Manduca sexta. J Insect Physiol 56:774-9
Mercer-Haines, Nancy; Fioravanti, Carmen F (2008) Hymenolepis diminuta: mitochondrial transhydrogenase as an additional site for anaerobic phosphorylation. Exp Parasitol 119:24-9
Vandock, Kurt P; Smith, Stan L; Fioravanti, Carmen F (2008) Midgut mitochondrial transhydrogenase in wandering stage larvae of the tobacco hornworm, Manduca sexta. Arch Insect Biochem Physiol 69:118-26
Park, J P; Fioravanti, C F (2006) Catalysis of NADH-->NADP+ transhydrogenation by adult Hymenolepis diminuta mitochondria. Parasitol Res 98:200-6
Mercer, N A; McKelvey, J R; Fioravanti, C F (1999) Hymenolepis diminuta: catalysis of transmembrane proton translocation by mitochondrial NADPH-->NAD transhydrogenase. Exp Parasitol 91:52-8
Fioravanti, C F; Walker, D J; Sandhu, P S (1998) Metabolic transition in the development of Hymenolepis diminuta (Cestoda). Parasitol Res 84:777-82
Walker, D J; Burkhart, W; Fioravanti, C F (1997) Hymenolepis diminuta: mitochondrial NADH --> NAD transhydrogenation and the lipoamide dehydrogenase system. Exp Parasitol 85:158-67

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