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

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DOI

  • Yudong Wang, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261.
  • ,
  • Johan Palmfeldt
  • Niels Gregersen
  • Alexander M Makhov, Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261.
  • ,
  • James F Conway, Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261.
  • ,
  • Meicheng Wang, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261.
  • ,
  • Stephen P McCalley, Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15261.
  • ,
  • Shrabani Basu, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261.
  • ,
  • Hana Alharbi, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261.
  • ,
  • Claudette St Croix, Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261.
  • ,
  • Michael J Calderon, Center for Rare Disease Therapy, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224.
  • ,
  • Simon Watkins, Center for Rare Disease Therapy, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224.
  • ,
  • Jerry Vockley, Center for Rare Disease Therapy, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224., University of Pittsburgh School of Medicine, University of Pittsburgh Graduate School of Public Health

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.

Original languageEnglish
JournalJournal of Biological Chemistry
Volume294
Issue33
Pages (from-to)12380-12391
Number of pages12
ISSN0021-9258
DOIs
Publication statusPublished - Aug 2019

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