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Metabolic Cardiology
Published in Stephen T. Sinatra, Mark C. Houston, Nutritional and Integrative Strategies in Cardiovascular Medicine, 2022
In the process of mitochondrial respiration and the genesis of ATP, not all the oxygen is converted to carbon dioxide and water. Three to five percent of the oxygen is generated from breakdown products known as free radicals. Because mitochondrial DNA has sparse defensive mechanisms, it is vulnerable to these unstable, unpaired electrons typical of free radical oxidative stress. So, it is essential to repair and support vulnerable mitochondrial activity from the relentless free radical stress of mitochondrial respiration that can negatively impact tissue and organ function.
Oxygen Transport
Published in James N. Cobley, Gareth W. Davison, Oxidative Eustress in Exercise Physiology, 2022
P.N. Chatzinikolaou, N.V. Margaritelis, A.N. Chatzinikolaou, V. Paschalis, A.A. Theodorou, I.S. Vrabas, A. Kyparos, M.G. Nikolaidis
Many researchers believe that all oxygen is used in mitochondrial respiration to produce ATP (Hill et al., 2012; Pittman, 2016). This notion is even more widely spread among exercise physiologists because skeletal muscle cells are rich in mitochondria and the energy-centric point of view prevails. However, it is now known that certain enzymes consume oxygen (e.g., oxygenases) and are localized mostly in the cytoplasm and not mitochondria (Romero et al., 2018). The most well-characterized enzymes consuming oxygen for purposes other than respiration are NADPH oxidases, NO synthases, xanthine oxidase, cyclooxygenases and lipoxygenases (Wagner, Venkataraman and Buettner, 2011). These enzymes have been found to be expressed in skeletal muscle in diverse cellular locations (Gomez-Cabrera et al., 2005; McConell et al., 2012; Henríquez-Olguin et al., 2019). As their activity increases during exercise, they become important consumers of oxygen in cases of increased contractile activity.
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
Acting as a tight barrier to all ions and molecules from the matrix and intermembrane space, the IMM utilizes a proton gradient to drive ATP synthesis. Embedded in the IMM are a series of large enzyme complexes, which generate this proton gradient, collectively termed the electron transport system (ETS) (Figure 26.1). Once liberated from metabolic substrates, electrons are shuttled through the ETS via NADH dehydrogenase (Complex I) or succinate dehydrogenase (SDH; Complex II). Electrons are then carried by the mobile electron carrier ubiquinone (coenzyme Q or CoQ) to cytochrome c reductase (Complex III) before being transferred to cytochrome c, with cytochrome c oxidase (COX; Complex IV) eventually receiving the electrons. Complex IV enables O2 to accumulate four electrons, which generates one molecule of H2O. The drop in free energy that occurs drives proton pumping at Complexes I, III, and IV from the matrix into the mitochondrial intermembrane space. Complex II only transfers electrons to coenzyme Q and does not help generate the proton gradient. The proton redistribution established by mitochondrial respiration maintains and modulates the IMM proton gradient, which drives the formation of ATP via mitochondrial ATP synthase (Complex V). Interestingly, the organization of mitochondrial cristae is tightly linked to the location of ETS enzyme complexes embedded in the IMM (64).
Recent advances in delivering RNA-based therapeutics to mitochondria
Published in Expert Opinion on Biological Therapy, 2022
Yuma Yamada, Sen Ishizuka, Manae Arai, Minako Maruyama, Hideyoshi Harashima
There have been reports in recent years that cytoplasmic RNA is transported into mitochondria through mitochondrial membrane transporters [28–30]. Attempts have been made to carried out to utilize this type of therapy, successfully maintaining the mitochondrial translation machinery by complementing mitochondria with normal tRNA in mutant cells by allotopic expression from the nucleus [31–33]. In these studies, it was reported that the mitochondrial respiratory activities were restored in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode (MELAS) cells after the treatment with a transfection reagent mixed with a tRNALeu derivative corresponding to the A3243G mutation in the mtDNA [33]. An A-to-G transition mutation at nucleotide pair 3243 in the mitochondrial tRNALeu(UUR) was found to be the primary cause of MELAS [34]. Karicheva and coworkers transfected pDNA coding wild type mitochondrial tRNA into cells of MELAS patients by lipofection and achieved mitochondrial delivery of the therapeutic RNA via allotopic expression. As a result, the mitochondrial translation was improved in the patient cells, and the levels of mitochondrial DNA-encoded respiratory complexes subunits were increased, thus restoring mitochondrial respiration [33].
Pathological mechanisms of abnormal iron metabolism and mitochondrial dysfunction in systemic lupus erythematosus
Published in Expert Review of Clinical Immunology, 2021
Chris Wincup, Natalie Sawford, Anisur Rahman
Aside from its role in hemopoiesis, iron has an essential role in mitochondrial function [32]. Mitochondria are specialized organelles that conduct a wide array of vital cellular process, most notably known for their key role in energy metabolism via the production of adenosine triphosphate [ATP]. The generation of ATP is dependent upon oxidative phosphorylation [OXPHOS] that results from a series of metabolic processes that are broadly referred to as mitochondrial respiration. The primary site of this reaction is across the electron transport chain [ETC] on the inner mitochondrial membrane [as summarized in Figure 1]. The ETC is comprised of five individual complexes [I–V], which drive protons across the membrane in order to generate an electrochemical gradient that is required for the conversion of adenosine diphosphate [ADP] to ATP via the fifth complex [also known as ATP synthase]. Iron plays an important role in complexes I, II, and II, where it is contained within iron-sulfur [IS] clusters in the ferrous [Fe2+] state. Clinically, abnormalities relating to IS clusters have been shown to play a pathogenic role in both Parkinson’s disease [33,34] and Friedreich ataxia [35]. However, before considering the role of abnormal iron metabolism in SLE, it is important to understand the way in which iron homeostasis is maintained in health.
Manganese dioxide nanosheets induce mitochondrial toxicity in fish gill epithelial cells
Published in Nanotoxicology, 2021
Cynthia L. Browning, Allen Green, Evan P. Gray, Robert Hurt, Agnes B. Kane
One major consequence of impaired mitochondrial respiration is inhibition of ATP production. Mitochondrial respiration is a major source of ATP production and contributes most of the cell’s energy (Attene-Ramos et al. 2015; Bonora et al. 2012). The Seahorse Mito Stress assay was utilized to calculate mitochondrial ATP production after exposure to MnO2 nanosheets, MnO2 microparticles or soluble MnCl2 (Figure 8). Mitochondrial ATP production was significantly inhibited after 48 h exposure to MnO2 nanosheets (Figure 8(B)). This inhibition of ATP production occurred in a concentration dependent manner. No effect on ATP production was observed following exposure to MnO2 microparticles or soluble MnCl2. Broader impacts of these functional changes are discussed next.