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Role of Tandem Mass Spectrometry in Diagnosis and Management of Inborn Errors of Metabolism
Published in P. Mereena Luke, K. R. Dhanya, Didier Rouxel, Nandakumar Kalarikkal, Sabu Thomas, Advanced Studies in Experimental and Clinical Medicine, 2021
Kannan Vaidyanathan, Sandhya Gopalakrishnan
Leigh syndrome is caused due to mutations in the protein coding gene, NDUFS4; (NADH dehydrogenase ubiquinone Fe-S protein 4). This protein is part of the mitochondrial Complex I, comprising 45 sub-units encoded by mitochondrial and nuclear genes. A recessive mouse phenotype was developed by inclusion of a transposable element into Ndufs4, and the resultant metabolite analysis of the model revealed increased hydroxyacylcarnitine species leading to imbalanced NADH/NAD(+) ratio which inhibited mitochondrial beta oxidation [53]. Proteomic analysis showed that the genes encoding acetyl-coA carboxylase beta, M-cadherin, calpain III, creatine kinase, glycogen synthase (GS), and sarcoplasmic reticulum calcium ATPase 1 (SERCA1) were down-regulated in patients with McArdle disease [54]. Statistically significant decreases were observed for five proteins following enzyme replacement therapy in patients with Fabry disease, namely, alpha(2)-HS glycoprotein, vitamin D-binding protein, transferrin, Ig-alpha-2 C chain, and alpha-2-antiplasmin [55].
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).
Carbon Dioxide Sequestration by Microalgae
Published in Gokare A. Ravishankar, Ranga Rao Ambati, Handbook of Algal Technologies and Phytochemicals, 2019
G.V. Swarnalatha, Ajam Shekh, P.V. Sijil, C.K. Madhubalaji, Vikas Singh Chauhan, Ravi Sarada
The CO2 supplementation up-regulated the gene encoding the components of pyruvate dehydrogenase complex, which is a multienzyme complex catalyzing the conversion of pyruvate into acetyl Co-A for TCA cycle. Similarly, it has been observed that the genes encoding nearly all the enzymes of TCA cycle were up-regulated by the CO2 supplementation which includes citrate synthase, isocitrate dehydrogenase, aconitase, oxoglutarate, dehydrogenase, succinyl-CoA synthetase, and fumarase. This implies that the CO2 supplementation improves the TCA cycle providing more NADH, ATP, and GTP. In addition, the genes encoded for the enzymes for anapleurotic reactions including PEP carboxylase and pyruvate carboxylase (catalyzing the carboxylation of PEP and pyruvate, respectively) were up-regulated on CO2 supplementation providing more oxaloacetate to replenish the TCA cycle. Correspondingly, the genes involved in electron transport and oxidative phosphorylation were significantly up-regulated on CO2 supplementation. This includes several subunits of the Complex I (NADH dehydrogenase), III (cytochrome bc1 complex), IV (cytochrome c oxidase), and ATP synthase leading improved electron flow to the O2 and increased ATP production. This indicated that CO2 supplementation led to increased metabolic energy to sustain the increased growth of microalgae (Peng et al. 2016; Zhu et al. 2017).
Association between sperm mitochondrial ND2 gene variants and total fertilization failure
Published in Systems Biology in Reproductive Medicine, 2018
Jin-Lan Zhang, Gen-Hong Mao, Xiao-Hui Huang, Hong-Yang Chang, Yi Zheng, Xue Cao
The sperm mitochondria are located in the sperm mid-piece. A single sperm contains approximately 22–72 mitochondria (Bahr and Engler 1970; Otani et al. 1988; St John et al. 2000; Gabriel et al. 2012). Mitochondria are the energy factories of a cell, playing a key role in energy production and maintenance of sperm motility (St John et al. 2000). In 1981, S. Anderson discovered that human mtDNA contains 16,569 base pairs, encoding 37 genes: 22 tRNA, 2 rRNA, and 13 peptide genes. The 13 proteins were the catalytic subunits of the enzyme complex containing ND1-ND6, ND4L, COXl- COX3, Cytb, ATPase6, and ATPase8, which are required for oxidative phosphorylation (OXPHOS), and they are a part of the electron transport chain (St John 2014). The OXPHOS system catalyzes the transfer of electrons from nicotinamide adenine dinucleotide (NADH) or reduced flavin adenine dinucleotide (FADH2) to molecular oxygen, the final electron acceptor. Electron transport is coupled to the transfer of protons that establishes an electrochemical gradient across the inner mitochondrial membrane, and this gradient is used to generate adenosine triphosphate (ATP) (Fromm et al. 2016). The ATP necessary for sperm motility is primarily derived from OXPHOS in mitochondria; therefore, OXPHOS and the ability to generate ATP directly affects sperm motility. Mitochondrial DNA (mtDNA) variants may lead to abnormalities in mitochondrial energy metabolism, thus, reducing sperm motility. The NADH dehydrogenase subunit 2 (ND2) is an mtDNA-coding gene and a subunit of NADH dehydrogenase. NADH dehydrogenase is the main component of complex I; it is directly involved in the electron and proton transfer in the respiratory chain to produce ATP through OXPHOS. In recent years, studies have also shown that both the deletion of and presence of variants of mitochondrially encoded cytochrome b (MTCYB) and mitochondrially encoded ATP synthase 6 (MTATP6) in sperm mitochondria might affect the sperm motility in adults (Feng et al. 2008). However, the specific mechanism of fertilization failure, and whether a mitochondrial gene-specific locus variant is a fertilization failure risk factor or an avoiding factor, is not clear.
The action of low doses of persistent organic pollutants (POPs) on mitochondrial function in zebrafish eyes and comparison with hyperglycemia to identify a link between POPs and diabetes
Published in Toxicology Mechanisms and Methods, 2020
Eun Ko, Dayoung Kim, Kitae Kim, Moonsung Choi, Sooim Shin
Alterations in the activity of mitochondrial respiration complexes are important indicators of mitochondrial function (Schapira et al. 1990; Hroudová et al. 2014). Using mitochondria isolated from glucose-immersed or non-immersed zebrafish, the activity of the mitochondrial respiratory complexes was measured and the enzyme activity for electron transfer reaction was calculated using Equation (1) (Spinazzi et al. 2012). As expected, most of the mitochondria isolated from glucose-immersed zebrafish exhibited enhanced activity of each complex compared to mitochondria isolated from zebrafish not immersed in glucose (Figure 3). The activity of mitochondrial complex I (NADH dehydrogenase) was measured by oxidation of NADH, functioning as electron donor to complex I. The rate of enzymatic activity of complex I in mitochondria of retina cells from glucose-immersed female and male zebrafish was slightly increased (Figure 3(A,B)). More significant differences were observed in females. The activity of mitochondrial complex II (succinate dehydrogenase) was assayed using succinate as electron donor to complex II and ubiquinone as electron acceptor from complex II. The reaction was monitored by the decrease in absorbance at 600 nm, which correlated with the reduction in DCPIP that accepts the electron from ubiquinone. Mitochondrial enzymatic activity complex II in retinal cells was enhanced in male zebrafish immersed in glucose but not in females (Figure 3(C,D)). The activity of complex III (cytochrome bc1 complex) was measured using ubiquinol as the electron donor to complex III and ferric cytochrome c as the electron acceptor from complex III. The increase in absorbance at 550 nm that indicates a reduction of cytochrome c was monitored. Similar changes were observed in the activities of mitochondrial complex III in retinal cells of female and male zebrafish immersed in glucose, and were greater at 7 days compared to 3 days (Figure 3(E,F)). The activity of complex IV (cytochrome c oxidase) was determined using ferrous cytochrome c as the electron donor to complex IV. The reaction was monitored by the decrease in absorbance at 550 nm, which correlates with the oxidation of cytochrome c. The activities of mitochondrial complex IV from both female and male zebrafish immersed in glucose were enhanced depending on the number of immersion days (Figure 3(G,H)). Regarding mitochondrial complexes I, II, III, and IV, a compensatory increase in functional activity was observed in glucose-immersed zebrafish. These results are consistent with the results of a compensatory increase in mitochondrial protein. Little differences in the activities of the mitochondrial complexes between male and female zebrafish were observed. It is supposed that our hyperglycemic zebrafish model, which reflects early stages of diabetes, is not influenced by sex-related differences in the endocrine system (Kajiwara et al. 2014).