Pathogenic mutations in the 5′ untranslated region of BCS1L mRNA in mitochondrial complex III deficiency

Gil-Borlado, M. Carmen; González-Hoyuela, Maritza; Blázquez, Alberto; García‐Silva, María Teresa; Gabaldón, Toni; Manzanares, J.; Vara, Julia; Martín, Miguel A.; Seneca, Sara; Arenas, Joaquı́n; Ugalde, Cristina

doi:10.1016/j.mito.2009.04.001

Cited by 29 publications

(19 citation statements)

References 21 publications

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“…To shed light on the metabolic alterations and signaling pathways affected by mitochondrial respiratory chain complex III enzyme deficiency, we first measured oxygen consumption rates (OCR), intracellular ATP levels and extracellular acidification rates (ECAR) in genetically and biochemically characterized primary skin fibroblasts from four healthy donors (C) and four complex III-deficient patients (P) harboring mutations in the BCS1L gene [15, 16, 18, 22]. Measurements showed a significant reduction of 30% in the oxygen consumption rates ( igure 1A) and a decrease of 70% in the intracellular ATP concentration (Figure 1B) of BCS1L mutant fibroblasts compared with the controls.…”

Section: Resultsmentioning

confidence: 99%

Differential proteomic profiling unveils new molecular mechanisms associated with mitochondrial complex III deficiency

Marín-Buera

García-Bartolomé

Morán

et al. 2015

Journal of Proteomics

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We have analyzed the cellular pathways and metabolic adaptations that take place in primary skin fibroblasts from patients with mutations in BCS1L, a major genetic cause of mitochondrial complex III enzyme deficiency. Mutant fibroblasts exhibited low oxygen consumption rates and intracellular ATP levels, indicating that the main altered molecular event probably is a limited respiration-coupled ATP production through the OXPHOS system. Two-dimensional DIGE and MALDI-TOF/TOF mass spectrometry analyses unambiguously identified 39 proteins whose expression was significantly altered in complex III-deficient fibroblasts. Extensive statistical and cluster analyses revealed a protein profile characteristic for the BCS1L mutant fibroblasts that included alterations in energy metabolism, cell signaling and gene expression regulation, cytoskeleton formation and maintenance, and intracellular stress responses. The physiological validation of the predicted functional adaptations of human cultured fibroblasts to complex III deficiency confirmed the up-regulation of glycolytic enzyme activities and the accumulation of branched-chain among other amino acids, suggesting the activation of anaerobic glycolysis and cellular catabolic states, in particular protein catabolism, together with autophagy as adaptive responses to mitochondrial respiratory chain dysfunction and ATP deficiency. Our data point to an overall metabolic and genetic reprogramming that could contribute to explain the clinical manifestations of complex III deficiency in patients.

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Section: Resultsmentioning

confidence: 99%

Differential proteomic profiling unveils new molecular mechanisms associated with mitochondrial complex III deficiency

Marín-Buera

García-Bartolomé

Morán

et al. 2015

Journal of Proteomics

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“…A number of functional mutations in BCS1L have been reported in patients with tubulopathy, encephalopathy, liver failure and the Björnstad syndrome [26, 27]. More recently, pathogenic mutations in the 5′ untranslated region of BCS1L mRNA have been identified, which were associated with decreased BCS1L mRNA and protein levels, and a complex III assembly impairment [28]. …”

Section: Mrc Structure Functions and Biogenesismentioning

confidence: 99%

Regulation of mitochondrial respiratory chain biogenesis by estrogens/estrogen receptors and physiological, pathological and pharmacological implications

Chen

Cammarata

Baines

et al. 2009

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

225

218

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There has been increasing evidence pointing to the mitochondrial respiratory chain (MRC) as a novel and important target for the actions of 17β-estradiol(E2) and estrogen receptors (ER) in a number of cell types and tissues that have high demands for mitochondrial energy metabolism. This novel E2-mediated mitochondrial pathway involves the cooperation of both nuclear and mitochondrial ERα and ERβ and their co-activators on the coordinate regulation of both nuclear DNA- and mitochondrial DNA-encoded genes for MRC proteins. In this paper, we have: 1) comprehensively reviewed studies that reveal a novel role of estrogens and ERs in the regulation of MRC biogenesis; 2) discussed their physiological, pathological and pharmacological implications in the control of cell proliferation and apoptosis in relation to estrogen-mediated carcinogenesis, anticancer drug resistance in human breast cancer cells, neuro-protection for Alzheimer’s disease and Parkinson’s disease in brain, cardiovascular protection in human heart and their beneficial effects in lens physiology related to cataract in the eye; and 3) pointed out new research directions to address the key questions in this important and newly emerging area. We also suggest a novel conceptual approach that will contribute to innovative regimines for the prevention or treatment of a wide variety of medical complications based on E2/ER-mediated MRC biogenesis pathway.

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“…(2) GRACILE syndrome (MIM] 603358), a Finnish-heritage disease caused by the homozygous p.S78G mutation [Fellman, 2002;Visapaa et al, 2002], which is characterized by fetal growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death; and (3) complex III deficiency in neonates or infants presenting with encephalopathy, alone or in combination with visceral involvement de Lonlay et al, 2001;De Meirleir et al, 2003;Fernandez-Vizarra et al, 2007;Gil-Borlado et al, 2009].…”

Section: Introductionmentioning

confidence: 99%

Cellular pathophysiological consequences of BCS1L mutations in mitochondrial complex III enzyme deficiency

et al. 2010

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Mutations in BCS1L, an assembly factor that facilitates the insertion of the catalytic Rieske Iron‐Sulfur subunit into respiratory chain complex III, result in a wide variety of clinical phenotypes that range from the relatively mild Björnstad syndrome to the severe GRACILE syndrome. To better understand the pathophysiological consequences of such mutations, we studied fibroblasts from six complex III‐deficient patients harboring mutations in the BCS1L gene. Cells from patients with the most severe clinical phenotypes exhibited slow growth rates in glucose medium, variable combined enzyme deficiencies, and assembly defects of respiratory chain complexes I, III, and IV, increased H2O2 levels, unbalanced expression of the cellular antioxidant defenses, and apoptotic cell death. In addition, all patients showed cytosolic accumulation of the BCS1L protein, suggestive of an impaired mitochondrial import, assembly or stability defects of the BCS1L complex, fragmentation of the mitochondrial networks, and decreased MFN2 protein levels. The observed structural alterations were independent of the respiratory chain function and ROS production. Our results provide new insights into the role of pathogenic BCS1L mutations in mitochondrial function and dynamics. Hum Mutat 31:–12, 2010. © 2010 Wiley‐Liss, Inc.

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Pathogenic mutations in the 5′ untranslated region of BCS1L mRNA in mitochondrial complex III deficiency

Cited by 29 publications

References 21 publications

Differential proteomic profiling unveils new molecular mechanisms associated with mitochondrial complex III deficiency

Differential proteomic profiling unveils new molecular mechanisms associated with mitochondrial complex III deficiency

Regulation of mitochondrial respiratory chain biogenesis by estrogens/estrogen receptors and physiological, pathological and pharmacological implications

Cellular pathophysiological consequences of BCS1L mutations in mitochondrial complex III enzyme deficiency

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