Infantile mitochondrial encephalomyopathy with unusual phenotype caused by a novel BCS1L mutation in an isolated complex III-deficient patient

Blázquez, Alberto; Gil-Borlado, M. Carmen; Morán, María; Verdú, Alfonso; Cazorla-Calleja, María Rosario; Martín, Miguel A.; Arenas, Joaquı́n; Ugalde, Cristina

doi:10.1016/j.nmd.2008.11.016

Cited by 46 publications

(22 citation statements)

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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%

“…So far, the vast majority of mutations leading to complex III deficiency have been localized to the nuclear BCS1L gene, which encodes a mitochondrial inner membrane translocase necessary for the import and insertion of the RISP subunit into complex III [11]. BCS1L mutations lead to three main clinical phenotypes [12]: (1) Björnstad Syndrome, an autosomal recessive disorder characterized by sensorineural hearing loss and pili torti [13]; (2) GRACILE Syndrome, a Finnish-heritage disease caused by the homozygous p.Ser78Gly mutation [14], which is characterized by fetal growth retardation, aminoaciduria, cholestasis, iron overload, lactic acidosis, and early death; and (3) Complex III deficiency in neonates, infants or adults presenting with liver disease and lactic acidosis, alone or in combination with encephalopathy and visceral involvement [6, 15-21]. …”

Section: Introductionmentioning

confidence: 99%

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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%

Section: Introductionmentioning

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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“…Fatigue severity also differs between prostate cancer patients with XRT and without XRT [8]. While there have been a limited number of interventions suggested to address fatigue, the only one that has an adequate evidence based to date is exercise [11]. Thus, healthcare professionals attempting to assist patients in addressing this critical source of distress have few strategies that can be helpful.…”

Section: Archives In Cancer Research Issn 2254-6081mentioning

confidence: 99%

Association between Mitochondrial Bioenergetics and Radiation- Related Fatigue: A Possible Mechanism and Novel Target

Hsiao¹

2015

Arch Can Res

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Background: Fatigue is one of the cancer symptoms most often reported by patients receiving radiation therapy (XRT). Understanding the mechanism behind the development of cancer-related fatigue will enable the design of novel interventions for radiation-induced fatigue. This research proposal is designed to determine the association between mitochondrial bioenergetics and fatigue in prostate cancer patients receiving XRT.

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“…They range from the least severe Björnstad syndrome with neurosensory hearing loss and pili torti, 58,59 a neurologic disease with muscle weakness and optic atrophy 60 to manifestations with encephalopathy, liver failure or tubulopathy, or combinations thereof. 45,61–65 Manifestations with neonatal onset usually present with hepatopathy (V. Fellman and H. Kotarsky, in this issue), the most severe being the GRACILE (growth restriction, aminoaciduria, cholestasis, iron overload, lactic acidosis and early death) syndrome, caused by a homozygous missense mutation (S78G). 66 The phenotype is strikingly consistent, 67 presenting with severe fetal growth restriction, lactacidosis and early death, further described in this issue (V. Fellman).…”

Section: Complex IIImentioning

confidence: 99%

Mitochondrial disorders caused by mutations in respiratory chain assembly factors

Díaz

Kotarsky

Fellman

et al. 2011

Seminars in Fetal and Neonatal Medicine

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Summary Mitochondrial diseases involve the dysfunction of the oxidative phosphorylation (OXPHOS) system. This group of diseases presents with heterogeneous clinical symptoms affecting mainly organs with high energy demands. Defects in the multimeric complexes comprising the OXPHOS system have a dual genetic origin, mitochondrial or nuclear DNA. Although many nuclear DNA mutations involve genes coding for subunits of the respiratory complexes, the majority of mutations found to date affect factors that do not form part of the final complexes. These assembly factors or chaperones have multiple functions ranging from cofactor insertion to proper assembly/stability of the complexes. Although significant progress has been made in the last few years in the discovery of new assembly factors, the function of many remains elusive. Here, we describe assembly factors or chaperones that are required for respiratory chain complex assembly and their clinical relevance.

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Infantile mitochondrial encephalomyopathy with unusual phenotype caused by a novel BCS1L mutation in an isolated complex III-deficient patient

Cited by 46 publications

References 9 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

Association between Mitochondrial Bioenergetics and Radiation- Related Fatigue: A Possible Mechanism and Novel Target

Mitochondrial disorders caused by mutations in respiratory chain assembly factors

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