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Clinical Manifestation of Mitochondrial Disorders in Childhood
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Leigh syndrome (Leigh, 1951) itself has two different meanings. The first represents the radiological or pathological findings of focal bilaterally symmetrical lesions, especially in the thalamus and brainstem regions. The other broadens this meaning to the clinical unit also known as subacute necrotizing encephalomyelopathy. Genetically, LS is very heterogenous and should be defined in by specific mutation or protein deficit where possible, as some particular may specifically differ in their clinical manifestation (e.g., SURF1 or pyruvate-dehydrogenase complex deficiency). In general, LS may be caused by deficits of respiratory chain complex subunits (complex I, II, IV, and V) and their cofactors (e.g., co-enzyme Q10), mutations in nDNA (e.g., SCO2, SURF1), mtDNA encoded tRNA, or the pyruvate dehydrogenase complex (Loeffen et al., 2000; Finsterer, 2008). Mitochondrial respiratory chain complex I (nicotinamide adenine dinucleotide-ubiquinone oxidoreductase) is the largest enzymatic complex of the mitochondrial respiratory chain. Defects in complex I due to nuclear DNA mutations are one of the most frequent casuses of LS. Various mutations in subunits of complex I encoded by nDNA (NDUFV1, NDUFV2, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS7, and NDUFS8 were reported (Marin et al., 2013).
Mitochondrial DNA Mutations and Mitochondrial Diseases
Published in Sara C. Zapico, Mechanisms Linking Aging, Diseases and Biological Age Estimation, 2017
Although 72 of the 85 subunits that form the respiratory chain complexes are encoded in the nucleus, mutations in such genes are rare. This might be a reflection of the highly deleterious nature of these mutations, which would result in lethality during embryogenesis. To date, mutations have been described in subunits of complex I (NDUFS 1, 2, 3, 4, 7 and 8, NDUFV1 and 2, and NDUFA1 and 11), associated with Leigh syndrome, encephalomyopathy, leukodystrophy and the four subunits of complex II (SDHA, B, C and D) associated with Leigh syndrome and ataxia in the case of the A subunit, and more rarely paraganglioma and feocromocitoma in the case of subunits B, C, and D. Mutations have also been described in complex III subunits UQCRB and UQCRQ associated with hypoglycemia, lactic acidosis and severe psychomotor delay with extra pyramidal signs, as well as a mutation in the complex IV (COX6B1) associated with childhood encephalomyopathy (Zhu et al. 2009).
Gene expression study of mitochondrial complex I in schizophrenia and paranoid personality disorder
Published in The World Journal of Biological Psychiatry, 2018
Arvin Haghighatfard, Sarah Andalib, Mozhdeh Amini Faskhodi, Soha Sadeghi, Amir Hossein Ghaderi, Shadi Moradkhani, Jalal Rostampour, Zeinab Tabrizi, Ali Mahmoodi, Talie Karimi, Zakieh Ghadimi
Gene expression studies of mitochondrial complex I help to clarify the pattern of bioenergetics effects in behaviour and psychiatric disorders. Several studies which considered the gene expression of the largest subunits of mitochondrial complex I presented it as potential peripheral biomarker for SCZ (Taurines et al. 2010; Akarsu et al. 2014). The present study examined gene expression of whole subunits in complex I in two psychiatric disorders for the first time, and detected a pattern of gene expression alterations including up- and down-regulations showing the importance of small subunits as well. This is the first gene expression study in PPD. Shared gene expression patterns of both disorders support the hypothesis of a similarity in pathophysiology of PPD and SCZ. Eighteen candidate genes were detected in SCZ and 11 genes in PPD; all of the candidate genes found in PPD were among the 18 differentially expressed genes found in SCZ and their alteration directions were the same in both disorders. These findings confirmed role of genomic core subunits in SCZ. Down-regulation of NDUFS7 and NDUFS8 along with up-regulation of NDUFS1, NDUFV1 and NDUFV2 were detected in both SCZ and PPD patients. Deregulation of these five subunits from 14 core subunits may cause abnormal structured complex I in neural cells, which leads to abnormal energetic state and altered neural activity. None of the seven mitochondrial genes showed a change in expression, which may reduce the importance of a maternal pattern in the heritance of SCZ and PPD. Over-expression of several supernumerary subunits was detected in SCZ and PPD patients. As oxidative stress is increased in psychiatric disorders, it may relate to the role of supernumerary subunits in protection against oxidative stress. Under-expression of five supernumerary subunits was detected in SCZ. Under-expression of NDUFB11 (which is only under-expressed in supernumerary subunits in PPD patients) was reported in brain tissue samples from SCZ patients (Huang et al. 2014). Also, down-regulation of the NDUFA1 gene was reported in progressive neurodegenerative diseases, including Alzheimer’s disease (Fernandez‐Moreira et al. 2007).
Quantitative analysis of the global proteome in lung from mice with blast injury
Published in Experimental Lung Research, 2020
Ying Liu, Yunen Liu, Changci Tong, Peifang Cong, Xiuyun Shi, Lin Shi, Mingxiao Hou, Hongxu Jin, Yongli Bao
According to our results, ROS and oxidative damage were detected in blast-injury mice. ROS are produced in mitochondria as a by-product of ATP production through oxidative phosphorylation. To our excitement, oxidative phosphorylation was also significantly enriched in the blast-injury mice according to proteomics analysis. Therefore, we detected the protein changes of oxidative phosphorylation in depth mechanism research.16,17 Our studies revealed the changes of oxidative phosphorylation including the NADH dehydrogenase, F-type ATPase, Cytochrome C reductase and Cytochrome C in the lung of blast-injury mice. Using Western blotting, we confirmed the change of several proteins, such as NDUFV1, NDUFA4, NDUFB3, NDUFB5, NDUFB6, and COX. Oxidative phosphorylation occurs in the inner mitochondrial membrane.18 It is the coupling reaction that utilizes substrates derived from glucose, fatty acids, and amino acids to produce ATP, which is a main source of organism energy.19 The enzymes of the oxidative phosphorylation consist of different protein complexes; The function is to carry out electron transfer, H transfer, oxygen utilization, and produce H2O and ATP.20 Complex I is NADH-Q reductase; Complex II is succinic acid-Q reductase; Complex III is cytochrome reductase; Complex IV is cytochrome oxidase; Complex V is ATP synthase.21 In this study, NDUFV1, NDUFA4, NDUFB3, NDUFB5, NDUFB6 all belong to NADH dehydrogenase. Ndufv gene relevant to mitochondrial respiration. It is reported that the NADH-dependent generation of extracellular superoxide was prevented by knockdown of NDUFV.22 Cyt1 belongs to cytochrome c reductase. Cytochrome c reductase exists as a dimer, each monomer contains two cytochrome b(b562、b566), a cytochrome c1 and an iron-sulfur protein. The founction is to catalyze electron transfer from coenzyme Q to cytochrome c.23 COX belongs to cytochrome c oxidase. Cytochrome c oxidase is an enzyme at the end of the mitochondrial respiratory chain, it take part in the electron transport in the mitochondrial respiratory chain and be related to the production of reactive oxygen species.24 For each pair of electrons transferred, four protons are simultaneously pumped from the mitochondrial matrix to the membrane gap.25 ATP synthase is widely distributed in the inner membrane of mitochondria and participates in the ATP generation.26 The electron transfer to proton pumping across the mitochondrial inner membrane to generate a transmembrane electrochemical potential and interferes with energy metabolism.27 Furthermore, it is reported that the alterations in oxidative phosphorylation can be related to the change of oxidative stress and inflammatory processes.28 The respiratory chain complex I and complex III are the sites of ROS generation during oxidative phosphorylation.29 These are consist with our finding in blast-injury mice.