Mitochondrial fatty acid oxidation and the electron transport chain comprise a multifunctional mitochondrial protein complex.

Autor:	Wang Y; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261., Palmfeldt J; Research Unit for Molecular Medicine, Aarhus University Hospital, DK-8200 Aarhus, Denmark., Gregersen N; Research Unit for Molecular Medicine, Aarhus University Hospital, DK-8200 Aarhus, Denmark., Makhov AM; Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261., Conway JF; Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261., Wang M; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261., McCalley SP; Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15261., Basu S; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261., Alharbi H; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261., St Croix C; Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261., Calderon MJ; Center for Rare Disease Therapy, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224., Watkins S; Center for Rare Disease Therapy, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224., Vockley J; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261; Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15261; Center for Rare Disease Therapy, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224. Electronic address: gerard.vockley@chp.edu.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2019 Aug 16; Vol. 294 (33), pp. 12380-12391. Date of Electronic Publication: 2019 Jun 24.
DOI:	10.1074/jbc.RA119.008680
Abstrakt:	Three mitochondrial metabolic pathways are required for efficient energy production in eukaryotic cells: the electron transfer chain (ETC), fatty acid β-oxidation (FAO), and the tricarboxylic acid cycle. The ETC is organized into inner mitochondrial membrane supercomplexes that promote substrate channeling and catalytic efficiency. Although previous studies have suggested functional interaction between FAO and the ETC, their physical interaction has never been demonstrated. In this study, using blue native gel and two-dimensional electrophoreses, nano-LC-MS/MS, immunogold EM, and stimulated emission depletion microscopy, we show that FAO enzymes physically interact with ETC supercomplexes at two points. We found that the FAO trifunctional protein (TFP) interacts with the NADH-binding domain of complex I of the ETC, whereas the electron transfer enzyme flavoprotein dehydrogenase interacts with ETC complex III. Moreover, the FAO enzyme very-long-chain acyl-CoA dehydrogenase physically interacted with TFP, thereby creating a multifunctional energy protein complex. These findings provide a first view of an integrated molecular architecture for the major energy-generating pathways in mitochondria that ensures the safe transfer of unstable reducing equivalents from FAO to the ETC. They also offer insight into clinical ramifications for individuals with genetic defects in these pathways. (© 2019 Wang et al.)
Databáze:	MEDLINE
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