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Characterizing the molecular architecture of mitochondrial energy metabolism

ABSTRACT: The electron transfer chain is organized into inner mitochondrial membrane supercomplexes that promote substrate channeling and catalytic efficiency. This study shows that fatty acid oxidation enzymes physically interact with electron transfer chain supercomplexes at two points. The fatty acid oxidation trifunctional protein interacts with the NADH-binding domain of complex I of the electron transfer chain, while electron transfer flavoprotein dehydrogenase interacts with electron transfer chain complex III. These findings provide first view of an integrated molecular architecture for the major energy generating pathways in mitochondria.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart

SUBMITTER: Johan Palmfeldt

LAB HEAD: Johan Palmfeldt

PROVIDER: PXD010838 | Pride | 2019-07-31

REPOSITORIES: Pride

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			Action	DRS
	Maxquant_files_Wang_et_al.zip	Other
	Q3325-Yudong-s1-1.raw	Raw
	Q3327-Yudong-s1-2.raw	Raw
	Q3329-Yudong-s1-3.raw	Raw
	Q3331-Yudong-s1-4.raw	Raw

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Publications

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

Wang Yudong Y Palmfeldt Johan J Gregersen Niels N Makhov Alexander M AM Conway James F JF Wang Meicheng M McCalley Stephen P SP Basu Shrabani S Alharbi Hana H St Croix Claudette C Calderon Michael J MJ Watkins Simon S Vockley Jerry J

The Journal of biological chemistry 20190624 33

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 ...[more]

PMID: 31235473

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Project description:Combining mass spectrometry based chemical cross-linking and complexome profiling, we analyzed the interactome of heart mitochondria. We focused on complexes of oxidative phosphorylation and found that dimeric apoptosis inducing factor 1 (AIFM1) forms a defined complex with ~10% of monomeric cytochrome c oxidase (COX), but hardly interacts with respiratory chain supercomplexes. Multiple AIFM1 inter-crosslinks engaging six different COX subunits provided structural restraints to build a detailed atomic model of the COX-AIFM12 complex. Application of two complementary proteomic approaches thus provided unexpected insight into the macromolecular organization of the mitochondrial complexome. Our structural model excludes direct electron transfer between AIFM1 and COX. Notably however, the binding site of cytochrome c remains accessible allowing formation of a ternary complex. The discovery of the previously overlooked COX-AIFM12 complex and clues provided by the structural model hint at a role of AIFM1 in OXPHOS biogenesis and in programmed cell death.

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SC-XL supercomplex protects against electron transport chain defects and alleviates ischemic heart failure

Project description:According to the fluidity model, complexes of the electron transport chain (ETC) in the inner mitochondrial membrane partition between free complexes and supercomplexes. However, conclusive proof of the physiological requirement of supercomplex formation is lacking, and the mechanisms regulating their formation remain enigmatic. Here, we show that genetic perturbations affecting the biogenesis or maturation of ETC Complex III (CIII) stimulates the formation of a specialized extra-large supercomplex (SC-XL) with a predicted stoichiometry of CI2+CIII2. SC-XL formation increases mitochondrial cristae density and sustains normal ETC output despite a 70% reduction in electron flow through CIII, effectively rescuing mild to moderate CIII deficiency. Increasing the SC-XL:free CIII2 ratio significantly reduced CIII ROS production and propensity for CI ROS triggered by reverse electron transport, leading to enhanced ETC efficiency. Furthermore, higher SC-XL:free CIII2 ratio reprogrammed mitochondria towards fatty acid oxidation, enhancing endurance exercise capacity and protection against ischemic heart failure in mice. Our study reveals an unanticipated plasticity in the mammalian ETC to buttress against intrinsic perturbations via structural adaptations, and suggests that ETC reprogramming via controlled regulation of SC-XL formation is a potential therapeutic strategy for remediating diseases characterized by a decline in ETC bioenergetics and oxidative damage.

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Project description:The electron transfer flavoprotein dehydrogenase (ETFDH) is the bottleneck enzyme of fatty acid oxidation (FAO). We performed a TMT 6plex analysis on Antimycin A treated and ETFDH-ko myoblasts (compared to CRL).

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Mitochondria proteomics of murine kidney podocytes

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Loss of Mitochondrial Fatty Acid β-Oxidation Protein Short Chain Enoyl-CoA Hydratase Disrupts Oxidative Phosphorylation Protein Complex Stability and Function

Project description:Short chain enoyl-CoA hydratase 1 (ECHS1) is involved in the second step of mitochondrial fatty acid β-oxidation (FAO), catalysing the hydration of short chain enoyl-CoA esters to short chain 3-hyroxyl-CoA esters. Genetic deficiency in ECHS1 (ECHS1D) is associated with a specific subset of Leigh Syndrome, a disease typically caused by defects in oxidative phosphorylation (OXPHOS). Here, we examined the molecular pathogenesis of ECHS1D using a CRISPR/Cas9 edited human cell ‘knockout’ model and fibroblasts from ECHS1D patients. Transcriptome analysis of ECHS1 ‘knockout’ cells showed reductions in key mitochondrial pathways, including the TCA cycle, receptor mediated mitophagy and nucleotide biosynthesis. Subsequent proteomic analyses confirmed these reductions and revealed additional defects in mitochondrial oxidoreductase activity and fatty acid β-oxidation. Functional analysis of ECHS1 ‘knockout’ cells showed reduced mitochondrial oxygen consumption rates when metabolising glucose or OXPHOS complex I-linked substrates, as well as decreased complex I and complex IV enzyme activities. ECHS1 ‘knockout’ cells also exhibited decreased OXPHOS protein complex steady-state levels (complex I, complex III2, complex IV, complex V and supercomplexes CIII2/CIV and CI/CIII2/CIV). Patient fibroblasts exhibit varied reduction of mature OXPHOS complex steady-state levels, with defects detected in CIII2, CIV, CV and the CI/CIII2/CIV supercomplex. Overall, these findings highlight the contribution of defective OXPHOS function, in particular complex I deficiency, to the molecular pathogenesis of ECHS1D.

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