Molecular and Supramolecular Structure of the Mitochondrial Oxidative Phosphorylation System: Implications for Pathology

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.

Oxidative Dysregulation in Early Life Stress and Posttraumatic Stress Disorder: A Comprehensive Review

“…This metabolic pathway is called oxidative phosphorylation and embraces a transfer of electrons from electron donors to electron acceptors (i.e., oxygen) in redox reactions, which creates energy used to transform adenosine diphosphate (ADP) to ATP in a phosphorylation reaction [24]. Over 90% of the ATP required for the regular cell function is provided by the aerobic respiratory electron transport system of mitochondria (encompassing five multi-subunit enzyme complexes, Complex I-V) [25], while additional oxidation processes involve cytoplasmatic enzyme activity [e.g., nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), xanthine oxidase, and cytochromes P450] [24,26,27]. Both systems (i.e., mitochondrial and cytoplasmatic), can result in the production of free radicals, namely reactive oxygen species (ROS) [e.g., superoxide anion (O 2…”

“…•− ), hydrogen peroxide (H 2 O 2 ), hydroxyl radical (OH)], and reactive nitrogen species (RNS) [e.g., peroxynitrite (ONOO − ), nitric oxide (NO)] [24]. However, other processes, such as activation of the immune system, lipid peroxidation, ischemia, and trauma, can also contribute to ROS/RNS generation [28,29].…”

“…Normally, ROS/RNS levels are counter-regulated to optimum levels by enzymatic antioxidants [e.g., superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione reductase (GSH-Rd), thioredoxin (TXN), thioredoxin reductase (TXN-Rd), peroxiredoxin (PRX), paraoxonase (PON)-1] and non-enzymatic [e.g., glutathione (GSH), vitamins A, C, and E, selenium, lipoic acid, L-cysteine, L-carnitine, L-carnosine, homocysteine, retinol, a-tocopherol, heme oxygenase (HO)-1, ubiquinol, flavonoids, and carotenoid] antioxidants [24,39,40].…”

Vitamin K Vitamers Differently Affect Energy Metabolism in IPEC-J2 Cells

“…At present this connection is established with Crohn’s disease ( Schoon et al, 2001 ), celiac disease ( Djuric et al, 2007 ), and inflammatory bowel disease ( Nowak et al, 2014 ). Pathological conditions are often associated with impaired mitochondrial bioenergetics ( Nesci et al, 2021 ). Moreover, VK antagonists used in clinical therapy to prevent thromboembolism together with coadministration of other drugs can induce drug-drug interaction effects with VK malabsorption ( Takada et al, 2015 ).…”

A Multidrug Approach to Modulate the Mitochondrial Metabolism Impairment and Relative Oxidative Stress in Fanconi Anemia Complementation Group A

“…In FA cells, quercetin treatment caused a simultaneous recovery of electron transfer between Complexes I and III and the OxPhos activity reduction. Since the slowed-down electron transport chain and the enhanced efficiency in the electron transport reduce the oxidative stress production [38], quercetin treatment also reduced In addition, the expression of phosphorylated γ-H2AX, a marker of DNA doublestrand breaks, was evaluated by western blot analysis. Data show a trend similar to the reduction of cell death (Figure 7C).…”