Characterizing the Molecular Architecture of Mitochondrial Energy Metabolism

Presented By:

Presenter: Yudong Wang, PhD

Contact Information: Yudong.wang@chp.edu, 724-889-7440

Authors: Yudong Wang1, Johan Palmfeldt2, Neils Gregersen2, Alexander Makhov3, James F. Conway3,  Meicheng Wang4, Stephen P. McCalley5, Shrabani Basu5, Hana Alharbi1, Claudette St. Croix6, Mike Calderon6 Xuemei Zeng6, Simon Watkins6, Nathan Yates6, and Jerry Vockley1,5,7

Institutions:

1University of Pittsburgh School of Medicine, Department of Pediatrics, Pittsburgh, PA.

2Aarhus University Hospital, Aarhus, Denmark.

3University of Pittsburgh School of Medicine, Department of Structural Biology, Pittsburgh, PA.

4University of Pittsburgh School of Pharmacy, Pittsburgh, PA 15213

5University of Pittsburgh Graduate School of Public Health, Department of Human Genetics, Pittsburgh, PA 15213

6University of Pittsburgh School of Medicine, Department of Cell Biology, Pittsburgh, PA 15213

7Children’s Hospital of Pittsburgh, Center for Rare Disease Therapy, Pittsburgh, PA 15224

Body of Abstract:

In mitochondrial energetics, the electron transfer equivalents generated from fatty acid oxidation (FAO), QH2 and NADH, are subsequently transferred as substrates to the electron transport chain (ETC). Supercomplexes (SC), separated from mammalian cells, contain complex I, III, and IV. SC shows the importance in stabilizing individual complexes and enhances the electron transfer efficiency functions. We have recently shown that many of the functions of fatty acid oxidation are also contained in SC. Also, we shown SC display electron transfer start from oxidation of long chain CoA and to reduce cytochrome c, the electron acceptor of ETC. The activity of oxidation of C16 CoA is about 2.6 times higher by SC than pure VLCAD. Currently we provide more evidence to show the physical interaction between FAO and ETC. Cross link plus Co-IP shown two physical associations point between FAO and ETC. (a) ETFDH physically interacts with com III at Q reduction side. By means of a connecting com III ETFDH indirectly binds to com I in SC through com III. (b) Trifunctional protein (TFP) associates with NADH biding domain of com I. The reducing equivalents, QH2 and NADH, from FAO enter ETC at the     level of complexes III and I respectively. The physical interactions would prevent the QH2 and NADH from be oxidized during transportation. Funding the interaction between FAO and ETC reveal (a) individual energy metabolism pathways physically linked to each other for the electron transfer substrate and product transportation to meet the needs of the most efficient metabolism. (b) The abnormal of the enzyme in one pathway would affect the other as the existing     linkages among pathways.

Patients with deficiencies of either FAO or OXPHOS often show clinical and/or biochemical findings indicative of a disorder of the other pathway. Genetic disorders of FAO and OXPHOS are among the most frequent inborn errors of metabolism. Patients with deficiencies of either FAO or OXPHOS often show clinical and/or biochemical findings indicative of a disorder of the other pathway.