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Kinetics of integrated electron transfer in the mitochondrial respiratory chain: random collisions versus solid state electron channelling
No full textThe Interplay Between Respiratory Supercomplexes and ROS in Aging
Full text linkSignificance: The molecular mechanism of aging is still vigorously debated, although a general consensus
exists that mitochondria are significantly involved in this process. However, the previously postulated role of
mitochondrial-derived reactive oxygen species (ROS) as the damaging agents inducing functional loss in aging
has fallen out of favor in the recent past. In this review, we critically examine the role of ROS in aging in the
light of recent advances on the relationship between mitochondrial structure and function. Recent Advances:
The functional mitochondrial respiratory chain is now recognized as a reflection of the dynamic association of
respiratory complexes in the form of supercomplexes (SCs). Besides providing kinetic advantage (channeling),
SCs control ROS generation by the respiratory chain, thus providing a means to regulate ROS levels in the cell.
Depending on their concentration, these ROS are either physiological signals essential for the life of the cell or
toxic species that damage cell structure and functions. Critical Issues: We propose that under physiological
conditions the dynamic nature of SCs reversibly controls the generation of ROS as signals involved in mitochondrial-
nuclear communication. During aging, there is a progressive loss of control of ROS generation so that
their production is irreversibly enhanced, inducing a vicious circle in which signaling is altered and structural
damage takes place. Future Directions: A better understanding on the forces affecting SC association would
allow the manipulation of ROS generation, directing these species to their physiological signaling role
Chapter 5. Mitochondrial Supercomplexes and ROS Regulation: Implications for Ageing
No full textCONTENTS
5.1 Introduction
5.2 Respiratory Supercomplexes: Structure and Function
5.2.1 Molecular Composition
5.2.2 Dynamic Nature and Kinetic Advantage of Supercomplexes
5.3 ROS Generation by Mitochondria
5.3.1 Respiratory Chain as a Source of ROS
5.3.1.1 Complex I
5.3.1.2 Complex III
5.3.1.3 Other Respiratory Enzymes
5.4 Mitochondrial ROS as Signals: Targets and Mechanisms
5.5 Regulation of Mitochondrial ROS Generation
5.5.1 Role of Mitochondrial Membrane Potential
5.5.2 Role of Post-Translational Modifications
5.5.3 Hypoxia and ROS Production
5.5.4 Role of Supercomplexes
5.6 ROS and Mitochondrial Quality Control
5.7 Implications for Ageing
5.7.1 Unifying Hypothesis Involving Supercomplex Destabilization in Agein
Coenzyme Q Function in Mitochondria
No full textIn this chapter we provide a review with a focus on the function of
Coenzyme Q (CoQ, ubiquinone) in mitochondria. The notion of a mobile pool of
CoQ in the lipid bilayer as the vehicle of electrons from respiratory complexes has
somewhat changed with the discovery of respiratory supramolecular units, in particular
the supercomplex comprising Complexes I and III; in such assembly the
electron transfer is thought to be mediated by direct channelling, and we provide
evidence for a kinetic advantage on the transfer based on random collisions. The
CoQ pool, however, has a fundamental function in establishing a dissociation equilibrium
with bound CoQ, besides being required for electron transfer from other
dehydrogenases to Complex III. CoQ bound to Complex I and to Complex III is also
involved in proton translocation; although the mechanism of the Q-cycle is well
established for Complex III, the involvement of CoQ in proton translocation by
Complex I is still debated. This review also briefly examines some additional roles
of CoQ, such as the antioxidant effect of its reduced form and its postulated action
at the transcriptional level
Complex I function in mitochondrial supercomplexes
Full text linkThis review discusses the functional properties of mitochondrial Complex I originating from its presence in an assembled form as a supercomplex comprising Complex III and Complex IV in stoichiometric ratios. In particular several lines of evidence are presented favouring the concept that electron transfer from Complex I to Complex III is operated by channelling of electrons through Coenzyme Q molecules bound to the supercomplex, in contrast with the hypothesis that the transfer of reducing equivalents from Complex I to Complex III occurs via random diffusion of the Coenzyme Q molecules in the lipid bilayer. Furthermore, another property provided by the supercomplex assembly is the control of generation of reactive oxygen species by Complex I. This article is part of a Special Issue entitled Respiratory Complex I, edited by Volker Zickermann and Ulrich Brandt
Coenzyme Q and respiratory supercomplexes: physiological and pathological implications
No full textIt was discovered over 60 years ago that the mitochondrial respiratory chain is constituted of a series of protein complexes imbedded in the inner mitochondrial membrane. Experimental evidence has more recently ascertained that the major respiratory complexes involved in energy conservation are assembled as supramolecular units (supercomplexes, SCs) in stoichiometric ratios. The functional role of SCs is less well defined, and still open to discussion. Several lines of evidence favour the concept that electron transfer from Complex I to Complex III operates by channelling of electrons through Coenzyme Q molecules bound to the SC I1III2IVn, in contrast with the previously accepted hypothesis that the transfer of reducing equivalents from Complex I to Complex III occurs via random diffusion of the Coenzyme Q molecules in the lipid bilayer. On the contrary, electron transfer from Complex III to Complex IV seems to operate, at least in mammals, by random diffusion of cytochrome c molecules between the respiratory complexes even if assembled in SCs. Furthermore, another property provided by the supercomplex assembly is the control of generation of reactive oxygen species by Complex I, that might be important in the regulation of signal transduction from mitochondria. This review discusses physiological and pathological implications of the supercomplex assembly of the respiratory chain
The mitochondrial respiratory chain is partly organized in a supercomplex assembly: kinetic evidence using flux control analysis
No full textTwo separate though interconneted route underlie NADH and succinate oxidation:kinetic evidence for different functional compartments of Coenzyme Q and/or Complex III.
No full textThe discovery of respiratory supercomplexes (SCs) led to the
proposal that electron transfer between complexes I and III (CI, CIII)
is mediated by channelling of Coenzyme Q (Q), with a kinetic
advantage on the transfer based on random collisions, whereas
electron transfer from CII to CIII obeys to the random collision model.
The evidence for Q channelling, however, is highly controversial [1,
2]. We have approached the problem in bovine heart submitochondrial
particles and in reconstituted proteoliposomes in which CI and
CIII are preserved as SC I1III2. We restricted electron transfer to the Q
area by studying NADH and succinate oxidation by exogenous
cytochrome c (cyt. c) as acceptor, thus avoiding the bottleneck of
endogenous cyt. c. Using this system we found the rates of NADH
and succinate oxidation by cyt. c to be almost completely additive.
The rate obtained by simultaneous addition of NADH and succinate
was much higher than that predicted for a homogeneous Q pool [3],
thus suggesting that NADH and succinate oxidation by cyt. c follow
two different routes. The NADH route presumably operates through
Q channelling in the SC I1III2. However Qpool molecules may
exchange with Qbound in SC, approaching the rates predicted for a
single pool, when the reducing pressure increases by strong CIII
inhibition or when detergents destabilize the SCs. The accessibility of
Qpool to SC I1III2 may be a physiological device to control electron
fluxes from different substrates and implies a dissociation equilibrium
of Qbound with the Q pool, by which the size of the pool
determines saturation of the binding site(s) in the SC. Thus bulk Qpool
has a role also in oxidation of NAD-linked substrates, providing a
rationale for the beneficial effect of exogenous Q supplementation on
mitochondrial bioenergetics.
References
1. JN Blaza et al. Proc Natl Acad Sci USA 111 (2014) 15735-40.
2. G Lenaz et al. BBA Bioenerg. (2016) Epub ahead of print.
3. A Kröger, M Klingenberg. Eur J Biochem. 34 (1973) 358-68
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