Supercomplex organization of the mitochondrial respiratory chain and the role of the Coenzyme Q pool: Pathophysiological implications

Abstract

In this review we examine early and recent evidence for an aggregated organization of the mitochondrial respiratory chain. Blue Native Electrophoresis suggests that in several types of mitochondria Complexes I, III and IV are aggregated as fixed supramolecular units having stoichiometric proportions of each individual complex. Kinetic evidence by flux control analysis agrees with this view, however the presence of Complex IV in bovine mitochondria cannot be demonstrated, presumably due to high levels of free Complex. Since most Coenzyme Q appears to be largely free in the lipid bilayer of the inner membrane, binding of Coenzyme Q molecules to the Complex I-III aggregate is forced by its dissociation equilibrium; furthermore free Coenzyme Q is required for succinate-supported respiration and reverse electron transfer. The advantage of the supercomplex organization is in a more efficient electron transfer by channelling of the redox intermediates and in the requirement of a supramolecular structure for the correct assembly of the individual complexes. Preliminary evidence suggests that dilution of the membrane proteins with extra phospholipids and lipid peroxidation may disrupt the supercomplex organization. This finding has pathophysiological implications, in view of the role of oxidative stress in the pathogenesis of many diseases.

Reactive oxygen species in redox cancer therapy

“…The elevated levels of ROS are mainly attributed to the following sources: (1) Increased metabolic activity and high mitochondrial energetics: Although cancer cells shift their glucose metabolism to anaerobic pathways even with sufficient oxygen supply (known as the Warburg effect), the higher than normal uptake of glucose still stimulates the mitochondrial energetics, which is believed to be related to elevated ROS production [28,29]; (2) alterations of the mitochondria ETC: Electrons linger on the complex increasing the possibility of being transferred to oxygen [19,30,31]; (3) the hypoxic condition of cancer leads to the activation of various key master proteins such as HIF-1, as mentioned above; (4) chronic inflammation and cytokine releasing [32]; (5) oncogenic signaling: The activation of c-Myc protein and its downstream signaling pathways can induce cellular ROS production [33] (Fig. 2).…”

Bioenergetic and Antioxidant Properties of Coenzyme Q10: Recent Developments

“…stable super complexes [8]. The advantage of this super complex organization would be a more efficient electron transfer by channelling of the redox intermediates.…”

“…Preliminary data suggest that alteration of the protein/phospholipid ratio and lipid peroxidation disaggregates the supercomplex organization with possible pathophysiological implications. Lenaz postulates [8] that in ageing, and in ischemic diseases, reactive oxygen species (ROS) produced by the mitochondrial respiratory chain induce a progressive peroxidation of mitochondrial phospholipids. This could lead to a dissociation of Complexes I-III aggregates and subsequent loss of facilitated electron channelling.…”

Combined defects in oxidative phosphorylation and fatty acid β-oxidation in mitochondrial disease

“…By forcing closer interactions between CI and CIII, the leakage of electrons to form superoxide is less likely. Indeed, oxidative stress is a common attribute in diseases where supercomplex assembly is disturbed (reviewed in [27,28]). …”