Structure and Mechanism of Respiratory III–IV Supercomplexes in Bioenergetic Membranes

Abstract

In the final steps of energy conservation in aerobic organisms, free energy from electron transfer through the respiratory chain is transduced into a proton electrochemical gradient across a membrane. In mitochondria and many bacteria, reduction of the dioxygen electron acceptor is catalyzed by cytochrome c oxidase (complex IV), which receives electrons from cytochrome bc 1 (complex III), via membrane-bound or watersoluble cytochrome c. These complexes function independently, but in many organisms they associate to form supercomplexes. Here, we review the structural features and the functional significance of the nonobligate III 2 IV 1/2 Saccharomyces cerevisiae mitochondrial supercomplex as well as the obligate III 2 IV 2 supercomplex from actinobacteria. The analysis is centered around the Q-cycle of complex III, proton uptake by CytcO, as well as mechanistic and structural solutions to the electronic link between complexes III and IV. CONTENTS 1. Introduction 9645 2. Complex III 9648 2.1. Catalytic Reaction and Quinone Binding 9649 2.2. The Bifurcated Electron Transfer 9650 2.2.1. Canonical Complex III 9650 2.2.2. M. smegmatis and C. glutamicum Supercomplexes 9651 2.3. Proton Release from the Q P Site 9651 2.3.1. Canonical Complex III 9651 2.3.2. M. smegmatis and C. glutamicum Supercomplexes 9651 3. Complex IV 9652 3.1. The Core Subunits 9653 3.2. The Catalytic Reaction and Proton Pathways 9653 3.3. Peripheral subunits of the S. cerevisiae CytcO 9654 3.4. The M. smegmatis CytcO 9654 3.5. Nonredox Active Metal Sites 9655 3.6. The Putative CytcO Dimer 9655 4. Complex III−IV Supercomplexes 9656 4.1. The S. cerevisiae Supercomplex 9656 4.2. Other (I)III 2 IV 1/2 Supercomplexes 9656 4.3. Cardiolipin in Supercomplexes 9657 4.4. Respiratory Supercomplex Factors 9658 4.5. Superoxide Dismutase in the M. smegmatis Supercomplex 9658 5. Interaction of Complexes III 2 and IV with Cytochrome c 9659 5.1. Cyt. c Binding to Complexes III and IV 9659 5.2. The Electronic Link between Complexes III and IV 5.2.1. Diffusion in 3D 5.2.2. Diffusion in 2D 5.2.3. Effects of Cox5/cyt. c Isoforms 5.2.4. Binding of cyt. c to Rcf1 6. Why Supercomplexes? 6.1. Changes in Structure or Activity upon Formation of Supercomplexes 6.2. Protein Distribution and Aggregation 6.3. Production of ROS 6.4. Free Energy Conservation 6.5. The Redox State and Binding of cyt. c

Effect of Pravastatin and Simvastatin on the Reduction of Cytochrome C

“…The apoptosis-inducing and cell cycle-inhibiting effect of simvastatin can also be useful. It is known that simvastatin increases the apoptosis of cancerous cells [ 3 , 4 , 5 ]. Based on our results, it is worth considering supplementing the simvastatin therapy of cancerous cells with Mg 2+ in order to aid the apoptotic processes.…”

“…This is provided through ionic and apolar bonds. Membrane-bound cytochrome c can only accept electrons from complex III, which it then passes on to complex IV for the reduction of molecular oxygen [ 5 ].…”

Structures of Tetrahymena ’s respiratory chain reveal the diversity of eukaryotic core metabolism

“…S2E) all suggest that Tt-SC I+III 2 is the minimal organization of Tt-CI (i.e., no free Tt-CI is present in T. thermophila mitochondrial membranes). Although obligatory supercomplexes have been seen between CIII 2 and CIV in actinobacteria ( 50 ), none have been previously observed in eukaryotes.…”

Structural basis of mammalian Complex IV inhibition by steroids

“…The D-pathway is composed of water molecules and conserved polar and protonatable residues, including Glu242 and Asp91, the latter giving the pathway its name (6). During each electron transfer from cytochrome c to the catalytic site, protons are pumped across the membrane through the D-pathway (for review, see (2,(7)(8)(9)(10)(11)). A third pathway (the H-pathway) has also been suggested for the mammalian CIV (8,12), but remains controversial because it is not present in the mitochondrial CIV from Saccharomyces cerevisiae (13) or bacterial CIVs (14).…”