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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).
Catalpol promotes mitochondrial biogenesis in chondrocytes
Published in Archives of Physiology and Biochemistry, 2022
Dan Chen, Jing Guo, Longguang Li
Since the nuclear DNA level is relatively stable, we concluded that a 30 μM catalpol treatment for 48 h increased more than half of the mitochondrial mass. We then measured the expression of five mitochondrial importing proteins encoding genes including translocase of outer mitochondrial membrane 22 (Tomm22), translocase of outer mitochondrial membrane 70 (Tomm70), mitochondrial import inner membrane translocase subunit 50 (Timm50), NADH dehydrogenase [ubiquinone] iron-sulphur protein 3 (NDUFS3), and ATP synthase subunit D (ATP5d) by the PCR method. It showed that the same dose and time of catalpol treatment increased twofold expression of all these genes. Third, we measured the expression of mitochondrial protein cytochrome B and the result again confirmed that catalpol increased the expression of cytochrome B (Figure 3(C)) by 1.7-fold high. These experiments indicate that catalpol promotes mitochondrial biogenesis in chondrocytes.
Effects of psychoactive drugs on cellular bioenergetic pathways
Published in The World Journal of Biological Psychiatry, 2021
Chiara C. Bortolasci, Briana Spolding, Srisaiyini Kidnapillai, Mark F. Richardson, Nina Vasilijevic, Sheree D. Martin, Laura J. Gray, Sean L. McGee, Michael Berk, Ken Walder
After genome-wide correction for multiple testing using FDR, valproate significantly increased the expression of NDUFA4 (q = 0.019) and NDUFAF4 (q = 0.004) from Complex 1, COX5A (q = 0.010) from Complex 4 and ATP5B (q = 0.00045) from Complex 5. Quetiapine increased the expression of NDUFA6-AS1 (q = 0.039, Complex 1), UQCRC2 (q = 0.0019, Complex 3) and COX7A2L (q = 0.00027, Complex 4). Quetiapine also decreased the expression of NDUFA1 (q = 0.025), NDUFA12 (q = 0.041), NDUFAF4 (q = 0.0037), NDUFB3 (q = 0.0053), NDUFC2 (q = 0.0086), NDUFS1 (q = 0.00014), NDUFS2 (q = 0.0029), NDUFS3 (q = 2.3E-06) and NDUFS5 (q = 0.0015) from Complex 1, as well as SDHA (q = 0.023, Complex 2), UQCR10 (q = 0.0060), UQCR11 (q = 0.0045) and UQCRC2 (q = 0.0019) from Complex 3, COX6B1 (q = 0.022) and COX7A2L (q = 0.00027, Complex 4), and ATP5A1 (q = 0.025), ATP5B (q = 5.1E-09), ATP5F1 (q = 0.00017), ATP5G1 (q = 0.00056), ATP5H (q = 0.0085), ATP5J (q = 0.048) and ATP5J2 (q = 0.015) from Complex 5. Lithium increased the expression of ATP5J2 (q = 0.028, Complex 5), while lamotrigine did not significantly affect expression of any of the OXPHOS genes measured.
Misconnecting the dots: altered mitochondrial protein-protein interactions and their role in neurodegenerative disorders
Published in Expert Review of Proteomics, 2020
Mara Zilocchi, Mohamed Taha Moutaoufik, Matthew Jessulat, Sadhna Phanse, Khaled A. Aly, Mohan Babu
ß-amyloid, TAU and their associated signaling pathways are mainly involved in the impairment of mt dynamics linked to AD pathology. For example, while the interaction between ß-amyloid and hyperphosphorylated TAU and DRP1 hyper-activates DRP1 to accelerate mt fragmentation [12,13], hyperphosphorylated TAU inhibits the anterograde axonal transport through the activation of GSK3 and protein phosphatase-1 (PP1) [194], and disruption of mt axonal trafficking trap C-Jun-amino-terminal kinase-interacting protein 1 (JIP1) via TAU [195]. In addition to this, mt homeostasis is also impacted in AD patients. Truncated TAU binds directly to Parkin and UCHL1, causing an aberrant recruitment of these proteins to the mt surface and an increase in Parkin-dependent mt disposal [196]. Conversely, human wildtype and mutant TAUP301L interact with Parkin and trap this protein into the cytoplasm, impeding its translocation to the mt surface following mt depolarization. The cytosolic binding between TAU and Parkin impairs mitophagy, thus causing an accumulation of damaged organelles [197]. Notably, post-translational modification of mt proteins, as shown in phosphoproteomics studies, showcase phosphorylation as key modulator of mt functions, the alteration of which is often associated with NDs. Tools such as fluorescent phosphospecific Pro-Q Diamond dye have been used to map overall phosphorylation alterations in AD-impacted brain regions, revealing altered phosphorylation levels of the mt matrix proteins such as NDUFS3, IMMT, and MDH2. This underscores the connectivity between altered mt phosphorylation and AD [198,199].