Wang Y 2019 J Biol Chem

Wang Y, Palmfeldt J, Gregersen N, Makhov AM, Conway JF, Wang M, McCalley SP, Basu S, Alharbi H, St Croix C, Calderon MJ, Watkins S, Vockley J (2019) Mitochondrial fatty acid oxidation and the electron transport chain comprise a multifunctional mitochondrial protein complex. J Biol Chem 294:12380-91. doi: 10.1074/jbc.RA119.008680

» PMID: 31235473 Open Access

Wang Y, Palmfeldt J, Gregersen N, Makhov AM, Conway JF, Wang M, McCalley SP, Basu S, Alharbi H, St Croix C, Calderon MJ, Watkins S, Vockley J (2019) J Biol Chem

Abstract: 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.

• Bioblast editor: Gnaiger E

• See Complex_II_ambiguities#CII_and_fatty_acid_oxidation

Selected quotes and comments

Gnaiger E (2023-09-07)

• The FAO-generated NADH and QH₂ are potentially exposed to oxidation in the reactive environment of the mitochondrial matrix and rely on safe transfer of electron-reducing equivalents from NADH and QH₂ to ETC to generate ATP.

Comment: If electron flavoprotein dehydrogenase (ETFDH) is recognized as a mtIM-bound respiratory Complex (CETFDH), then it is clear that QH₂ is generated within the membrane-bound electron transfer system (mETS), ETF but not QH₂ transfers reducing equivalents to the mETS, and QH₂ in the mtIM is not exposed to the mt-matrix.

• Thus, a suitable physical interaction is required to ensure the safe transfer of electron equivalents from FAO to ETC.

Comment: It is helpful to distinguish FAO and beta-oxidation, since FAO includes (quote) 'transport of substrates into mitochondria through carnitine palmitoyltransferases I and II (CPTI and CPTII) linked by a carnitine-acylcarnitine translocase', beta-oxidation, and downstream transfer of reducing equivalents to O₂ as the final electron acceptor.

Labels:

Enzyme: Complex I, Complex III, Supercomplex 

Pathway: F