Impaired Complex I Assembly in a Leigh Syndrome Patient with a Novel Missense Mutation in the ND6 Gene
ABSTRACT We describe a novel mutation in the ND6 gene (T14487C) in a patient with Leigh syndrome. Biochemical analyses indicated a low complex I activity in the patient's fibroblasts but normal values in muscle and liver. Cybrid clones showed a specific complex I defect that correlates with the mutant heteroplasmy levels. Additionally, we demonstrate an altered mobility and a decrease in the levels of fully assembled complex I in the patient's fibroblasts and cybrids, suggesting that the mutation has a profound effect on complex I assembly and/or stability.
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- "Mimicking other mutations common to LHON also significantly altered the rates of ETC assembly (Pello et al., 2008). Another consequence of altered mtDNA sequence is the interdependency of the ETC Complexes for their stability within the mitochondrial membrane (Lamantea et al., 2002; Ugalde et al., 2003; Acin-Perez et al., 2004; Edgar et al., 2009). Collectively these studies point to the critical role of mtDNA fidelity has on the mitochondrial function within the myocardium. "
ABSTRACT: Aims: Alcoholic cardiomyopathy (ACM) presents as decreased myocardial contractility, arrhythmias and secondary non-ischemic dilated cardiomyopathy leading to heart failure. Mitochondrial dysfunction is known to have a significant role in the development and complications of ACM. This study investigated if chronic ethanol feeding promoted myocardial mitochondrial topoisomerase dysfunction as one underlying cause of mitochondrial DNA (mtDNA) damage and mitochondrial dysfunction in ACM. Methods: The impact of chronic ethanol exposure on the myocardial mitochondria was examined in both neonatal cardiomyocytes using 50 mM ethanol for 6 days and in rats assigned to control or ethanol feeding groups for 4 months. Results: Chronic ethanol feeding led to significant (P < 0.05) decreases in M-mode Fractional Shortening, ejection fraction, and the cardiac output index as well as increases in Tau. Ethanol feeding promoted mitochondrial dysfunction as evidenced by significantly decreased left ventricle cytochrome oxidase activity and decreases in mitochondrial protein content. Both in rats and in cultured cardiomyocytes, chronic ethanol presentation significantly increased mtDNA damage. Using isolated myocardial mitochondria, both mitochondrial topoisomerase-dependent DNA cleavage and DNA relaxation were significantly altered by ethanol feeding. Conclusion: Chronic ethanol feeding compromised cardiovascular and mitochondrial function as a result of a decline in mtDNA integrity that was in part the consequence of mitochondrial topoisomerase dysfunction. Understanding the regulation of the mitochondrial topoisomerases is critical for protection of mtDNA, not only for the management of alcoholic cardiomyopathy, but also for the many other clinical treatments that targets the topoisomerases in the alcoholic patient.Alcohol and alcoholism (Oxford, Oxfordshire). Supplement 05/2014; 49(4). DOI:10.1093/alcalc/agu029
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- "Lethal infantile mitochondrial disease Calvo et al. (2010) c.1158C>G Leukoencephalopathy Breningstall et al. (2008) c.1294G>C + c.989- 990del-2 LS Benit et al. (2001) c.86C>T NDUFV2 Encephalomyopathy NADH-dehydrogenase module Hinttala et al. (2005) IVS2 + 5 + 8delGTTA Hypertrophic Cardiomyopathy and Encephalopathy Bénit et al. (2003a,b), Pagniez-Mammeri et al. (2009) a All the listed mutations induce a CI disassembly except for c.1336G>A/NDUFS2 (Ngu et al., 2012). of subcomplexes in patient-derived cell cultures (Solano et al., 2003; Ugalde et al., 2003). Moreover, a partial CI disassembly has been described in cells harboring LS pathogenic mutations , namely m.10158T>C, m.10191T>C and m.10197G>A in MT-ND3 (Kirby et al., 2004a; McFarland et al., 2004). "
ABSTRACT: Respiratory chain complex I (CI) dysfunctions have been recognized as one of the most frequent causes of mitochondrial neuro-muscular disorders. Moreover, latest reports reveal that CI impairment is a major contributing factor in many other pathological processes, including cancer. In fact, energy depletion, oxidative stress and metabolites unbalance are frequently associated with CI functional and structural alterations. The occurrence of mitochondrial DNA (mtDNA) mutations is a shared feature in neuro-muscular diseases and cancer; however, the two diverging phenotypes arise depending on the mutation type (disassembling versus non-disassembling mutations), the mutant load and the cytotype. In this review, we unify our knowledge on CI impairment caused by mutations in structural CI genes and assembly chaperones, both in mitochondrial disorders and cancer, stratifying such mutations based on their functional versus structural effects. We summarize shared and specific metabolic consequences of CI dysfunction in these pathologies, which allow us to draw two parallel roads that lead to different clinical outcomes. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy.The international journal of biochemistry & cell biology 06/2012; 45(1). DOI:10.1016/j.biocel.2012.05.016 · 4.05 Impact Factor
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- "Mistakes in Mitochondrial Proteins Cause Aging of complexes I, III, and IV of the respiratory chain is critically dependent on mtDNA-encoded core subunits (Lamantea et al., 2002; Saraste, 1990; Ugalde et al., 2003). In addition, a decrease in the assembly of complex III or complex IV may directly interfere with the stability of complex I in mtDNA mutator mice by disrupting supercomplex formation. "
ABSTRACT: The mtDNA mutator mice have high levels of point mutations and linear deletions of mtDNA causing a progressive respiratory chain dysfunction and a premature aging phenotype. We have now performed molecular analyses to determine the mechanism whereby these mtDNA mutations impair respiratory chain function. We report that mitochondrial protein synthesis is unimpaired in mtDNA mutator mice consistent with the observed minor alterations of steady-state levels of mitochondrial transcripts. These findings refute recent claims that circular mtDNA molecules with large deletions are driving the premature aging phenotype. We further show that the stability of several respiratory chain complexes is severely impaired despite normal synthesis of the corresponding mtDNA-encoded subunits. Our findings reveal a mechanism for induction of aging phenotypes by demonstrating a causative role for amino acid substitutions in mtDNA-encoded respiratory chain subunits, which, in turn, leads to decreased stability of the respiratory chain complexes and respiratory chain deficiency.Cell metabolism 09/2009; 10(2):131-8. DOI:10.1016/j.cmet.2009.06.010 · 17.57 Impact Factor