Mitochondrial Respiratory Complex
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Mitochondrial Respiratory Complex
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Mitochondrial Respiratory Complex
- 2. Respirasomes/Supercomplexes • Enzymes of the mitochondrial respiratory chain assemble into larger, supramolecular structures • Functionally active and necessary for forming stable respiratory complexes. • Variety of species and tissues • Rat brain, liver, kidney, skeletal muscle, heart, bovine heart, human skin fibroblasts, fungi, plants, and C. elegans Protein Cell. 2013 Aug; 4(8): 582–590.
- 3. multi History Protein Cell 2016, 7(12):854–865
- 4. Classes of Protein Complexes • Four multi-subunit complexes Complex I (NADH:ubiquinone oxidoreductase) Complex II (succinate dehydrogenase) Complex III (cytochrome bc1 complex) Complex IV (cytochrome c oxidase) Protein Cell. 2013 Aug; 4(8): 582–590.
- 5. Function • The mitochondrial respiratory chain complexes reside in the inner mitochondrial membrane or cristae and have important roles in energy conversion. • Three complexes (CI, CIII and CIV) collectively establish the proton gradient across the inner mitochondrial membrane for complex V (CV, ATP synthase) to synthesize ATP. • The respiratory chain complexes and CV together form the oxidative phosphorylation (OXPHOS) system. Protein Cell. 2013 Aug; 4(8): 582–590.
- 6. Mitochondrial Oxidative Phosphorylation System (OXPHOS)
- 7. Dysfunction • Reactive oxygen or nitrogen species, impairs oxidative phosphorylation, reduces the membrane potential and ATP synthesis, and leads to impaired NAD+/NADH ratio. • Human diseases including Alzheimer’s and Parkinson’s diseases, multiple sclerosis, Friedreich’s ataxia and amyotrophic lateral sclerosis. Protein Cell. 2013 Aug; 4(8): 582–590.
- 8. Respirasome Protein Cell 2016, 7(12):854–865
- 12. Cryo-EM Structure of the Respirasome J Gu et al. Nature 1–5 (2016
- 13. Nature 2016 volume537, pages639–643
- 15. Structure of Mammalian Respiratory Supercomplex I1III2IV1 Cell 167, 1598–1609, December 1, 2016
- 18. Conclusion • Collectively, the structural information reported in these studies establishes the organizing principles of the respiration supercomplexes, reveals protein-protein and protein-cofactor binding interactions with exquisite details, suggests an alternative testable model for electron transfer, and paves the road for future in-depth understanding of the OXPHOS system as a whole.
Editor's Notes
- supercomplexes containing complexes I, III, and IV were proposed by a few groups to form respiratory strings, in which different supercomplex forms are arranged in an ordered linear pattern along the inner mitochondrial membrane cristae
- Mitochondrial OXPHOS The OXPHOS consists of 5 protein complexes and 2 electron carriers embedded in the inner mitochondrial membrane
- These defects perturb a large va-riety of metabolic processes and are implicated in a plethoraof human diseases
- The structure of respirasome from porcine heart at a resolution of 5.4 Å. (A) front view; (B) back view; (C) top view; (D) bottom view. The relations between the views are indicated by the angles. But due to the limited resolution, Dudkina were not able to recognize the cavity responsible for ubiquinone-channeling. The respirasome, designated as supercomplex SC(I + III2 + IV), consists of the 44 distinct subunits of Complex I (CI), the 22 subunits of dimeric Complex III (CIII), and one Complex IV (CIV) unit of 14 subunits. This represents only one of a myriad of respiratory supercomplexes.
- (A) The (I + III2 + IV) respirasome couples the oxidation of NADH to reduction of molecular oxygen. CI (outlined in blue) oxidizes NADH and transfers two electrons through its FMN cofactor and seven of its eight Fe-S clusters to reduce ubiquinone (Q) to ubiquinol (QH2). The dimeric CIII (outlined in green) oxidizes QH2 and transfers one electron to cytochrome c via a heme and a Fe-S cluster and the second electron is used to reduce Q in the Q cycle of proton pumping. CIV (outlined in red) receives four electrons from successive cytochrome c transfers and electrons pass through a binuclear copper A center, a heme a moiety to a heterobimetallic copper B-heme a3 center for the 4 electron reduction of molecular oxygen. IMM is the inner mitochondrial membrane, IMS is the intermembrane space and matrix is the space enclosed by the inner membrane.
- (B) This side view of the respirasome highlights additional CI cofactors. The ACP protein SDAP-β and the corresponding LYRM protein, NDUFB22 (A, purple/dark purple) and ACP protein SDAP-α and its corresponding LYRM protein, NDUFB14 (B, purple/magenta) are associated by a C:10 acyl chain on the phosphopantetheine (PPT) cofactor of each ACP. These ACP-LYRM dimers provide a potential regulatory link between fatty acid biosynthesis and respiration. A NADPH molecule bound to NDUFA9 (C, yellow) and zinc ion bound to NDUFS6 (D, orange) may act as redox sensors for CI function.
- The IMS view of the respirasome shows subunits in all three complexes that contain stabilizing disulfide bonds. Redox changes in these subunits may modulate the respirasome function. The disulfide subunits include COX6B (E, red) in complex CIV, UQCRH (F, green) in CIII, and CI subunits in blue NDUFB7 (G), NDUFB10 (H), NDUFA11 (I), NDUFS5 (J) and NDUFA8 (K).
- a, The side views along the membrane of the unsharpened density map (at 5σ contour level) of the respirasome with distinct regions labelled and indicated by black arrows. b, Same as d, but for the sharpened map filtered to a resolution of 5.4 Å (7σ contour level of CI and CIII; 5σ contour level of CIV). The transmembrane region is indicated by two dashed lines. M, matrix; IM, inner membrane; IMS, intermembrane space. c, Bottom view of the unsharpened map viewed from the intermembrane space. The black dashed lines indicate the boundaries between the complexes. The red dashed lines linked the centres of the transmembrane regions of three complexes. d, Selected z slices of the final sharpened map corresponding to the layers indicated by the numbered arrows in b. The arrays of transmembrane segments could be easily seen in subpanel 2. The positions of different complexes are indicated.
- Transparent surface representation of the segmented maps of different components, shown in three views along the membrane with different rotations. The structures of the core subunits and unassigned supernumerary components of CI are shown in cartoon representation and coloured in blue and cyan, respectively. The assigned subunits are coloured in different colours and indicated. CIII and CIV are coloured in golden and magenta, respectively. b, CI is shown the same as in a and with the assigned supernumerary components as indicated. The CIII dimer and CIV bind at the same side of the L-shaped CI, with their transmembrane domains essentially aligned to form a transmembrane disk. Compared to free CI, the CI in the respirasome is more compact because of interactions with CIII and CIV. The NDUFA11 and NDUFB9 supernumerary subunits of CI contribute to the oligomerization of CI and CIII.
- The MCI2III2IV2 forms a circular structure with the dimeric CIII located in the center, where it is surrounded by two copies each of CI and CIV. Analyses indicate that CII could insert into the gaps between CI and CIV to form a closed ring, which we termed the electron transport chain supercomplex. The structure not only reveals the precise assignment of individual subunits of human CI and CIII, but also enables future in-depth analysis of the electron transport chain as a whole.
- The mammalian respiratory SCI1III2IV1is the largest and mostcomplicated enzyme in the inner mitochondrial membrane. It hasa dimension of190 A ̊in height and 300 A ̊in length The complex III (CIII) dimer and complex IV (CIV) bind at the same side of the L-shaped complex I (CI).
- Several accessory or supernumerary subunits of CI, such as NDUFA11, NDUFB4, NDUFB8, and NDUFB9, directly contribute to the oligomerization of CI, CIII, and CIV. The structure reveals that the 14 core subunits of CI together with 30 accessory subunits form an integral unit to transfer two electrons from NADH to UQ. Four accessory subunits (NDUFA11, NDUFB4, NDUFB8, and NDUFB9) of CI mainly contribute to interactions with the CIII dimer through direct protein-protein interactions or through phospholipid molecules in the CI-CIII groove (Figure 5).
- gure 7. Electron Transfer Pathway in CI and CIII(A) Structural assignment of electron carriers in CI and CIII. The bottom panel shows a detailed arrangement of Qiand Qosites reported in previous studies. TheUQ2s shown in spheres are modeled into a Q-chamber in CI and the hypothetical Qoand Qibinding sites in CIII. The heme molecules are shown in sticks, and theFe-S clusters are shown in spheres. The image is viewed along the membrane. M, matrix; IM, inner membrane; IMS, intermembrane space.(B) Electron transfer and coupled H+transport mechanism. Electron trail from NADH in CI to Cyt.cin CIII is shown in blue solid line. An alternative electron trail isshown as a blue dashed line. Elements in the blue dashed circle are movable electron carriers. The transport of H+is shown as a green dashed line. The thicknessof mitochondrial inner membrane and the length of UQ are shown. The length of the electron trail from FMN to N2 in CI is10.3 nm. The distance from the UQ-binding pocket in CI to the Qisite in the distal CIII monomer is13 nm, while the distance to the Qisite in the proximal CIII monomer is11 nm. Distances aremeasured from our structure. The hemes and UQ molecules are shown as sticks, and the FeS clusters are shown as spheres.1606Cell167, 1598–1609, December 1, 2016