The Mitochondrial Respiratory Chain Is Partially Organized in a Supercomplex Assembly

The model of the respiratory chain in which the enzyme complexes are independently embedded in the lipid bilayer of the inner mitochondrial membrane and connected by randomly diffusing coenzyme Q and cytochrome c is mostly favored. However, multicomplex units can be isolated from mammalian mitochondria, suggesting a model based on direct electron channeling between complexes. Kinetic testing using metabolic flux control analysis can discriminate between the two models: the former model implies that each enzyme may be rate-controlling to a different extent, whereas in the latter, the whole metabolic pathway would behave as a single supercomplex and inhibition of any one of its components would elicit the same flux control. In particular, in the absence of other components of the oxidative phosphorylation apparatus (i.e. ATP synthase, membrane potential, carriers), the existence of a supercomplex would elicit a flux control coefficient near unity for each respiratory complex, and the sum of would be and of the flux control of the complexes in and in and to be rate-controlling a suggesting the existence of between the two whereas randomly that is for the absence of channeling and The model of the respiratory chain in which the enzyme complexes are independently embedded in the lipid bilayer of the inner mitochondrial membrane and connected by randomly diffusing coenzyme Q and cytochrome c is mostly favored. However, multicomplex units can be isolated from mammalian mitochondria, suggesting a model based on direct electron channeling between complexes. Kinetic testing using metabolic flux control analysis can discriminate between the two models: the former model implies that each enzyme may be rate-controlling to a different extent, whereas in the latter, the whole metabolic pathway would behave as a single supercomplex and inhibition of any one of its components would elicit the same flux control. In particular, in the absence of other components of the oxidative phosphorylation apparatus (i.e. ATP synthase, membrane potential, carriers), the existence of a supercomplex would elicit a flux control coefficient near unity for each respiratory complex, and the sum of would be and of the flux control of the complexes in and in and to be rate-controlling a suggesting the existence of between the two whereas randomly that is for the absence of channeling and on the of of the complexes the mitochondrial respiratory direct on the of the complexes in the inner mitochondrial for in the membrane are the model of a of the respiratory complexes and that of a supercomplex by between model of and the oxidative phosphorylation isolated as complexes and by the model of enzyme complexes in the lipid as in a by in of mitochondrial electron the of the that electron in mitochondrial on between diffusing Q and cytochrome and complexes independently embedded in the bilayer the of a between complexes and of of and isolated from from and and of of in and in mammalian mitochondria, and a model of the respiratory chain based on direct channeling between complexes and on In particular, of from two of and the of and as two by of in from the of a that two and different of The existence of for on between and of is the supercomplex to analysis is a of on the of complexes of the respiratory and to discriminate between and the of the of electron lipid and that Q coenzyme Q coenzyme Q in is a that from to in the coefficient of the a model of the mitochondrial by a of the respiratory complexes In from of cytochrome c in the mitochondrial respiratory chain complexes one respiratory control analysis that can on the of the respiratory a metabolic pathway is of the to which each enzyme is rate-controlling may be and the sum of the flux control for the different be to the other in a the metabolic pathway would behave as a single enzyme and inhibition of any one of the enzyme components would elicit the same flux control. 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on between diffusing Q and cytochrome and complexes independently embedded in the bilayer the of a between complexes and of of and isolated from from and and of of in and in mammalian mitochondria, and a model of the respiratory chain based on direct channeling between complexes and on In particular, of from two of and the of and as two by of in from the of a that two and different of The existence of for on between and of is the supercomplex In to analysis is a of on the of complexes of the respiratory and to discriminate between and the of the of electron lipid and that Q coenzyme Q coenzyme Q in is a that from to in the coefficient of the a model of the mitochondrial by a of the respiratory complexes In from of cytochrome c in the mitochondrial respiratory chain complexes one respiratory control analysis that can on the of the respiratory a metabolic pathway is of the to which each enzyme is rate-controlling may be and the sum of the flux control for the different be to the other in a the metabolic pathway would behave as a single enzyme and inhibition of any one of the enzyme components would elicit the same flux control. In particular, in a in which the respiratory chain is from other components of the oxidative phosphorylation apparatus (i.e. ATP synthase, membrane potential, and carriers), as the existence of a supercomplex would elicit a flux control coefficient near unity any of the respiratory and the sum of would be the in and in from using metabolic flux control analysis in and The the of a of and whereas the other respiratory complexes to be from from a from of the of in of and and by a as The of as by the of of cytochrome by Q in a and using as enzyme as the same and In particular, and c to that of membrane of and of cytochrome c for cytochrome as in cytochrome c by the of cytochrome c coefficient by the of in the of of of membrane by for and in the absence of to its to the of The of in the membrane by of a apparatus a and a of and flux control analysis by the whole respiratory chain and its single of the for for for and for The of by its inhibition of the of in a between and the of that the a inhibition of c to the in the and to a of one of whereas can The of and as The inhibition a on the of of using the control from the in the enzyme the of a of the of the of the inhibition of the flux to the of the inhibition of the of of the flux control in be in the of However, as a of the of the can be that the coefficient of each the of the to the from the by the of the as a of the inhibition of the single for the same from from a from of the of in of and and by a as The of as by the of of cytochrome by Q in a and using as enzyme as the same and In particular, and c to that of membrane of and of cytochrome c for cytochrome as in cytochrome c by the of cytochrome c coefficient by the of in the of of of membrane by for and in the absence of to its to the of The of in the membrane by of a apparatus a and a of and flux control analysis by the whole respiratory chain and its single of the for for for and for The of by its inhibition of the of in a between and the of that the a inhibition of c to the in the and to a of one of whereas can The of and as The inhibition a on the of of using the The control from the in the enzyme the of a of the of the of the inhibition of the flux to the of the inhibition of the of of the flux control in be in the of However, as a of the of the can be that the coefficient of each the of the to the from the by the of the as a of the inhibition of the single for the same for the in the and the of and in by The inhibition using is in The is for and in the on the the two are in the for to a of and The flux control coefficient by the of the is control of the complexes in by different of the respiratory chain in and c in a The flux control by using to the enzyme the two of a and the are in for the control coefficient for flux control coefficient for The of inhibition on the flux (i.e. that on the same of the of the in can be that the of the two inhibition The control coefficient of cytochrome is of that the of of cytochrome c and in two the of control by the enzyme of the respiratory chain in analysis of the metabolic flux control of and the respiratory chain by the of the c in in the of the of the two complexes. 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single and that the of in the the between the respiratory to randomly in the lipid bilayer of the the of the flux control of the in mitochondrial by of the metabolic flux and the enzyme analysis to the whole of to the in the of the of the the of the in the of to in the and to as by other be that be by that the of and is the as by of the of for in to the of the metabolic control for metabolic channeling can that enzyme and in the respiratory chain the sum of the control from in the of the electron is whereas to be randomly cytochrome c as a the same on the in the that and are in a the of membrane as by that is by the supercomplex in for complexes of channeling to a enzyme from other a of channeling is the of and cytochrome c in the mitochondrial respiratory which a of the of a In and that the and in a and the that the of in the is that of to the be by the and to in mitochondrial and a supercomplex and as a single enzyme as one in the complexes that to in mitochondria, that is in the membrane the of a of the of in different mitochondrial a of the model of the mitochondrial respiratory chain its and that as a between and the in of is the can be that and are by that in isolated complexes. electron in the respiratory chain would a channeling be by on metabolic of the is that the of the inner mitochondrial membrane that of other by its of the membrane and to of the membrane The between a from the of by the of the respiratory from to and that the between complexes may be the of that of complexes of a in a in and that of c The of a of in the of the mitochondrial to for the respiratory a in of the existence of of respiratory complexes and would on the that on the of that a between the respiratory and the of which mammalian are in of and in mitochondrial are to by flux control the of are the existence of between and whereas of of any of the other respiratory complexes be The is of one a of is on a a a to is that the for the electron components is of to to to based on for 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metabolic control for metabolic channeling can that enzyme and in the respiratory chain the sum of the control from in the of the electron is whereas to be randomly cytochrome c as a the same on the in the that and are in a the of membrane as by that is by the supercomplex in for complexes of channeling to a enzyme from other a of channeling is the of and cytochrome c in the mitochondrial respiratory which a of the of a In and that the and in a and the that the of in the is that of to the be by the and to in mitochondrial and a supercomplex and as a single enzyme as one in the complexes that to in mitochondria, that is in the membrane the of a of the of in different mitochondrial a of the model of the mitochondrial respiratory chain its and that as a between and the in of is the can be that and are by that in isolated complexes. electron in the respiratory chain would a channeling be by on metabolic of the is that the of the inner mitochondrial membrane that of other by its of the membrane and to of the membrane The between a from the of by the of the respiratory from to and that the between complexes may be the of that of complexes of a in a in and that of c The of a of in the of the mitochondrial to for the respiratory a in of the existence of of respiratory complexes and would on the that on the of that a between the respiratory and the of which mammalian are in of and in mitochondrial are to by flux control the of are the existence of between and whereas of of any of the other respiratory complexes be The is of one a of is on a a a to is that the for the electron components is of to to to based on for in the by the in that of the and of the complex, as the of the membrane by cytochrome is that by is that any in mitochondrial to a of in The of is for and for