Abstract
Under aerobic conditions, mitochondrial oxidative phosphorylation (OXPHOS) converts the energy released by nutrient oxidation into ATP, the currency of living organisms. The whole biochemical machinery is hosted by the inner mitochondrial membrane (mtIM) where the protonmotive force built by respiratory complexes, dynamically assembled as super-complexes, allows the F1FO-ATP synthase to make ATP from ADP + Pi. Recently mitochondria emerged not only as cell powerhouses, but also as signaling hubs by way of reactive oxygen species (ROS) production. However, when ROS removal systems and/or OXPHOS constituents are defective, the physiological ROS generation can cause ROS imbalance and oxidative stress, which in turn damages cell components. Moreover, the morphology of mitochondria rules cell fate and the formation of the mitochondrial permeability transition pore in the mtIM, which, most likely with the F1FO-ATP synthase contribution, permeabilizes mitochondria and leads to cell death. As the multiple mitochondrial functions are mutually interconnected, changes in protein composition by mutations or in supercomplex assembly and/or in membrane structures often generate a dysfunctional cascade and lead to life-incompatible diseases or severe syndromes. The known structural/functional changes in mitochondrial proteins and structures, which impact mitochondrial bioenergetics because of an impaired or defective energy transduction system, here reviewed, constitute the main biochemical damage in a variety of genetic and age-related diseases.
Highlights
This review intends to outline the major structural and functional aspects of mitochondrial bioenergetics that are at the basis of changes leading to pathology; in particular, we will deal with recent advances of the supramolecular structure of the respiratory chain complexes and of F1FO-ATP synthase/hydrolase; for this reason, this review will not analyze other important aspects in much detail such as the intimate mechanisms of electron transfer and proton translocation on one hand, and the analysis of the individual pathologies on the other
If channeling occurs between CI and CIII by the common intermediate CoQ, the redox groups involved in CoQ reduction by CI and CoQH2 re-oxidation in CIII must be in close contact in order to form a driving pathway containing CoQ itself; similar reasoning applies to cyt. c between CIII and CIV
Using specific inhibitors to establish the extent of metabolic control exerted by each individual complex over the entire NADH-dependent respiration, we demonstrated that CI and CIII are both rate-limiting, since they exhibit flux control coefficients (FCC) close to 1, behaving as a single enzymatic unit (e.g., supramolecular structure (SCs) I1III2); we concluded that electron transfer through CoQ is accomplished by channeling between CI and CIII [63]
Summary
The advancement of molecular medicine has pinpointed the role of mitochondria in the etiology and pathogenesis of most common chronic diseases [1,2,3,4], so much that the term “Mitochondrial Medicine” has been proposed [5] and widely used [6,7,8,9]. In recent years it has been raised again due to a series of novel findings assigning new roles to mitochondria in molecular and cell biology, such as mitochondrial DNA and mitochondrial genetics, the role of mitochondria in generation of reactive oxygen species (ROS) and in cell signaling, in cellular quality control and apoptosis (programmed cell death) These newly discovered functions are strictly intertwined with the central role of electron transfer and ATP synthesis. This review intends to outline the major structural and functional aspects of mitochondrial bioenergetics that are at the basis of changes leading to pathology; in particular, we will deal with recent advances of the supramolecular structure of the respiratory chain complexes and of F1FO-ATP synthase/hydrolase; for this reason, this review will not analyze other important aspects in much detail such as the intimate mechanisms of electron transfer and proton translocation on one hand, and the analysis of the individual pathologies on the other
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