Abstract
The mitochondrial respiratory chain encompasses four oligomeric enzymatic complexes (complex I, II, III and IV) which, together with the redox carrier ubiquinone and cytochrome c, catalyze electron transport coupled to proton extrusion from the inner membrane. The protonmotive force is utilized by complex V for ATP synthesis in the process of oxidative phosphorylation. Respiratory complexes are known to coexist in the membrane as single functional entities and as supramolecular aggregates or supercomplexes (SCs). Understanding the assembly features of SCs has relevant biomedical implications because defects in a single protein can derange the overall SC organization and compromise the energetic function, causing severe mitochondrial disorders. Here we describe in detail the main types of SCs, all characterized by the presence of complex III. We show that the genetic alterations that hinder the assembly of Complex III, not just the activity, cause a rearrangement of the architecture of the SC that can help to preserve a minimal energetic function. Finally, the major metabolic disturbances associated with severe SCs perturbation due to defective complex III are discussed along with interventions that may circumvent these deficiencies.
Highlights
Salvatore NesciThe mitochondria are cytosolic organelles of eukaryotic cells in charge of ATP production through the process of oxidative phosphorylation (OXPHOS)
They are involved in an array of adaptive responses triggered by perturbations of intracellular homeostasis [10], orchestrating anabolic and catabolic reactions, which are finely adjusted according to different cytosolic conditions. All these interconnected functions are sustained by the activity of the “mitochondrial proteome”, estimated to contain at least 1000 [11] to 1500 [12] different proteins, 15% of which are directly involved in energy metabolism and the OXPHOS system
Unlike the oxidation of NADH which only occurs via CI, FADH2 can be oxidized at the inner membrane mainly by CII, and by other less abundant proteins such as the glycerol-3-phosphate dehydrogenase [14], the electron transfer flavoprotein dehydrogenases [15,16,17], the dihydroorotate dehydrogenase [18], the choline dehydrogenase [19], the sulfide coenzyme Q (CoQ) reductase [20], and the proline dehydrogenase [21]
Summary
The mitochondria are cytosolic organelles of eukaryotic cells in charge of ATP production through the process of oxidative phosphorylation (OXPHOS). Mitochondria are implicated in the buffering of cytosolic calcium concentration [7], in generation of reactive oxygen species (ROS) [8], and in regulation and execution of different types of cell death [9] They are involved in an array of adaptive responses triggered by perturbations of intracellular homeostasis [10], orchestrating anabolic and catabolic reactions, which are finely adjusted according to different cytosolic conditions. Unlike the oxidation of NADH which only occurs via CI, FADH2 can be oxidized at the inner membrane mainly by CII, and by other less abundant proteins such as the glycerol-3-phosphate dehydrogenase [14], the electron transfer flavoprotein dehydrogenases [15,16,17], the dihydroorotate dehydrogenase [18], the choline dehydrogenase [19], the sulfide CoQ reductase [20], and the proline dehydrogenase [21]. This later, together with other FAD-linked enzymes, does not contribute to energy conservation
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