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Mitochondrial Dysfunction in Chronic Disease
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Christopher Newell, Heather Leduc-Pessah, Aneal Khan, Jane Shearer
Apart from ATP generation, the IMM is responsible for several other functions, including movement of ATP across the IMM via ADP/ATP translocase proteins (66), migration of proteins into the matrix through a translocase of the inner membrane (TIM) protein complexes (34), and transport of fatty acids into the mitochondrial matrix via carnitine acyltransferase (CAT) enzymes (9). In functional mitochondria, ATP synthase is arranged in a dimer at the hairpin of a cristae, while the cristae lumen is lined by ETS enzymes in supercomplexes (64). However, the cristae flatten with age, resulting in impaired ETS supercomplex activity, decreased ATP synthase activity, and culminate in IMM rupture and apoptosis (64). Contrarily, exercise has been shown to alter the fine structure of mitochondria resulting in increased mass and improved function (143).
Mitochondrial Dysfunction and Barth Syndrome
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Arianna F. Anzmann, Steven M. Claypool, Hilary Vernon
CL composes up to 20% of the phospholipid mass of the IMM and is critical for mitochondrial cristae formation, based on observations of abnormal IMM ultrastructure in CL-deficient models76–78. The mitochondrial cristae house the oxidative phosphorylation (OXPHOS) system. Therefore, it is not surprising that CL also plays a critical role in the efficiency and adaptability of the OXPHOS machinery. First, CL stabilizes the higher order assemblies of the individual respiratory complexes into respiratory supercomplexes (SCs), which are combinations of respiratory complexes I, III, and IV79–87. SC assembly is thought to increase the efficiency of electron transfer in OXPHOS, maximize OXPHOS function, minimize reactive oxygen species (ROS) production, and thereby reduce oxidative damage. Second, CL is proposed to act as a proton trap, restricting the diffusion of protons and funneling them toward ATP synthase to generate ATP88. Lastly, once ATP is formed by OXPHOS, it then passes across the IMM to the IMS via the ADP/ATP carrier. CL is needed for not only the stabilization of the carrier, but is also required for the association of the carrier with the OXPHOS SCs89,90. Besides the ADP/ATP carrier, CL also plays a plays a protective and stabilizing role for various mitochondrial carriers (Figure 3)91.
The Role of Students’ Social Identities in Fostering High-Quality Learning in Higher Education
Published in Kenneth I. Mavor, Michael J. Platow, Boris Bizumic, Self and Social Identity in Educational Contexts, 2017
Ana-Maria Bliuc, Peter Goodyear, Robert A. Ellis
Ultimately, the supercomplex world presents not challenges of knowing but of being. Traditionally, the main emphasis has been on intellectual development; but this is no longer enough. The human being consists of three distinct domains: knowing, self-identity, and action.
Telacebec: an investigational antibacterial for the treatment of tuberculosis (TB)
Published in Expert Opinion on Investigational Drugs, 2022
Telacebec binds to the QcrB subunit of the M. tuberculosis cytochrome bcc:aa3 supercomplex. The cytochrome bcc:aa3 is a dimeric complex comprising two bcc menaquinol reductases and aa3 oxidases [12,13]. The supercomplex is part of the pathogen’s electron transport chain (ETC) in the oxidative phosphorylation pathway. It is homologous to complexes III and IV found in the mammalian mitochondria ETC. The cytochrome bcc:aa3 supercomplex acts as a terminal oxidase in the ETC and functions to catalyze the transfer of electrons to molecular oxygen, reducing it to water. The complex also contributes to the proton motive force (pmf), which is essential for ATP synthesis as well as other enzymatic functions such as active transport of xenobiotics through efflux pumps [14]. The cytochrome bcc:aa3 is important for optimum growth in mycobacteria and deletion of the genes encoding the respiratory complex in M. tuberculosis resulted in a significant growth defect [15,16].
Novel insights into the pathogenesis of molecular subtypes of diffuse large B-cell lymphoma and their clinical implications
Published in Expert Review of Clinical Pharmacology, 2019
Until recently, signaling of BCR and MYD88 both causing oncogenic NF-κB signaling was thought to be independent and therefore the observation that especially patients with concomitant mutations of CD79B and MYD88 profit from ibrutinib treatment remained unclear [37]. A comprehensive molecular analysis of ibrutinib-sensitive cell lines and lymphoma biopsies revealed a new supercomplex formed by the BCR, MYD88, and TLR9 that colocalize in cytoplasmic endolysomes (termed My-T-BCR supercomplex) leading to NF-κB and mTOR signaling [48]. Especially in double mutant cell lines (MYD88 and CD79B mutations) the My-T-BCR was present and depletion of one of its elements disrupted its assembly and downstream signaling. Mass spectrometry of MYD88-proximal biotinylated proteins revealed that proteins such as mTOR, CARD11, BCL10, MALT1 are part of this complex suggesting that the earlier identified cytoplasmic aggregates containing CBM members might be part of this bigger My-T-BCR supercomplex bringing different pathways to one central site of oncogenic activation (Figure 1) [36]. Treatment with ibrutinib disrupts the assembly and signaling of the My-T-BCR and shows synergistic effects with mTOR inhibitors. Hence, detection of the My-T-BCR in lymphoma biopsies might predict responsiveness to ibrutinib and potentially other small molecule inhibitors.
When nature’s robots go rogue: exploring protein homeostasis dysfunction and the implications for understanding human aging disease pathologies
Published in Expert Review of Proteomics, 2018
Julie A. Reisz, Alexander S. Barrett, Travis Nemkov, Kirk C. Hansen, Angelo D’Alessandro
Another negative consequence of ROS accumulation is the activation of purine deaminases (e.g. AMP deaminase), which deplete the reservoir of high-energy phosphate purines, such as ATP. These actions also pave the way for the generation of pro-oxidants through purine catabolism, exemplified by the generation of hydrogen peroxide via xanthine oxidase [36]. ATP depletion is particularly deleterious in that it serves as the key energy source for maintaining proteostasis balance. A lack of adequate cellular ATP supply necessitates a shift toward the preservation of the most critical processes to maintain cellular homeostasis, thereby hindering ATP-dependent reactions in other nonessential roles such as the ubiquitin-proteasome protein degradation system [37]. Increased steady-state levels of ROS coupled with diminished ATP levels exacerbate the aging quality control mechanisms that impact many aspects of proteostasis. While further work is required to understand its role in age-associated dysregulation of proteostasis, modification of ETC efficiency through the maintenance of mitochondrial supercomplexes may provide a mechanism to minimize the damaging effects associated with these processes [38–40].