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1.
Mol Genet Metab ; 108(1): 102-5, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23206802

RESUMO

We report the second known family with a very rare, maternally inherited missense m.8851T>C mutation in the mitochondrial MTATP6 gene. A failure to thrive, microcephaly, psychomotor retardation and hypotonia were present in a 3-year-old girl with a high mtDNA mutation load (87-97%). Ataxia and Leigh syndrome were subsequently documented in a neurological examination and brain MRI. A muscle biopsy demonstrated decreased ATP synthase and an accumulation of succinate dehydrogenase products, indicating mitochondrial myopathy. Her 36-year-old mother (68% blood heteroplasmy) developed peripheral neuropathy and muscle weakness at the age of 22 years. Our findings extend the clinical and laboratory phenotype associated with the m.8851T>C mutation.


Assuntos
Mitocôndrias/metabolismo , ATPases Mitocondriais Próton-Translocadoras/genética , Músculos/patologia , Mutação , Animais , Biópsia , Pré-Escolar , Cães , Feminino , Humanos
2.
Biochem J ; 428(3): 363-74, 2010 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-20307258

RESUMO

Mammalian CcO (cytochrome c oxidase) is a hetero-oligomeric protein complex composed of 13 structural subunits encoded by both the mitochondrial and nuclear genomes. To study the role of nuclear-encoded CcO subunits in the assembly and function of the human complex, we used stable RNA interference of COX4, COX5A and COX6A1, as well as expression of epitope-tagged Cox6a, Cox7a and Cox7b, in HEK (human embryonic kidney)-293 cells. Knockdown of Cox4, Cox5a and Cox6a resulted in reduced CcO activity, diminished affinity of the residual enzyme for oxygen, decreased holoCcO and CcO dimer levels, increased accumulation of CcO subcomplexes and gave rise to an altered pattern of respiratory supercomplexes. An analysis of the patterns of CcO subcomplexes found in both knockdown and overexpressing cells identified a novel CcO assembly intermediate, identified the entry points of three late-assembled subunits and demonstrated directly the essential character as well as the interdependence of the assembly of Cox4 and Cox5a. The ectopic expression of the heart/muscle-specific isoform of the Cox6 subunit (COX6A2) resulted in restoration of both CcO holoenzyme and activity in COX6A1-knockdown cells. This was in sharp contrast with the unaltered levels of COX6A2 mRNA in these cells, suggesting the existence of a fixed expression programme. The normal amount and function of respiratory complex I in all of our CcO-deficient knockdown cell lines suggest that, unlike non-human CcO-deficient models, even relatively small amounts of CcO can maintain the normal biogenesis of this respiratory complex in cultured human cells.


Assuntos
Núcleo Celular/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Subunidades Proteicas/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/genética , Humanos , Subunidades Proteicas/genética , Interferência de RNA , RNA Mensageiro/metabolismo
3.
Eur J Hum Genet ; 22(3): 431-4, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23838601

RESUMO

Mitochondrial disorders are caused by defects in mitochondrial or nuclear DNA. Although the existence of large deletions in mitochondrial DNA (mtDNA) is well known, deletions affecting whole genes are not commonly described in patients with mitochondrial disorders. Based on the results of whole-genome analyses, copy number variations (CNVs) occur frequently in the human genome and may overlap with many genes associated with clinical phenotypes. We report the discovery of two large heterozygous CNVs on 22q13.33 in two patients with mitochondrial disorders. The first patient harboured a novel point mutation c.667G>A (p.D223N) in the SCO2 gene in combination with a paternally inherited 87-kb deletion. As hypertrophic cardiomyopathy (HCMP) was not documented in the patient, this observation prompted us to compare his clinical features with all 44 reported SCO2 patients in the literature. Surprisingly, the review shows that HCMP was present in only about 50% of the SCO2 patients with non-neonatal onset. In the second patient, who had mitochondrial neurogastrointestinal encephalopathy (MNGIE), a maternally inherited 175-kb deletion and the paternally inherited point mutation c.261G>T (p.E87D) in the TYMP gene were identified.


Assuntos
Cardiomiopatia Hipertrófica Familiar/genética , Proteínas de Transporte/genética , Variações do Número de Cópias de DNA , Pseudo-Obstrução Intestinal/genética , Encefalomiopatias Mitocondriais/genética , Proteínas Mitocondriais/genética , Mutação Puntual , Timidina Fosforilase/genética , Cardiomiopatia Hipertrófica Familiar/diagnóstico , Criança , Cromossomos Humanos Par 22/genética , Humanos , Lactente , Pseudo-Obstrução Intestinal/diagnóstico , Masculino , Encefalomiopatias Mitocondriais/diagnóstico , Chaperonas Moleculares , Distrofia Muscular Oculofaríngea , Oftalmoplegia/congênito
4.
Mol Biol Cell ; 23(6): 1010-23, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22262461

RESUMO

Mitochondrial ATPases associated with diverse cellular activities (AAA) proteases are involved in the quality control and processing of inner-membrane proteins. Here we investigate the cellular activities of YME1L, the human orthologue of the Yme1 subunit of the yeast i-AAA complex, using stable short hairpin RNA knockdown and expression experiments. Human YME1L is shown to be an integral membrane protein that exposes its carboxy-terminus to the intermembrane space and exists in several complexes of 600-1100 kDa. The stable knockdown of YME1L in human embryonic kidney 293 cells led to impaired cell proliferation and apoptotic resistance, altered cristae morphology, diminished rotenone-sensitive respiration, and increased susceptibility to mitochondrial membrane protein carbonylation. Depletion of YME1L led to excessive accumulation of nonassembled respiratory chain subunits (Ndufb6, ND1, and Cox4) in the inner membrane. This was due to a lack of YME1L proteolytic activity, since the excessive accumulation of subunits was reversed by overexpression of wild-type YME1L but not a proteolytically inactive YME1L variant. Similarly, the expression of wild-type YME1L restored the lamellar cristae morphology of YME1L-deficient mitochondria. Our results demonstrate the importance of mitochondrial inner-membrane proteostasis to both mitochondrial and cellular function and integrity and reveal a novel role for YME1L in the proteolytic regulation of respiratory chain biogenesis.


Assuntos
Proliferação de Células , Transporte de Elétrons , Metaloendopeptidases/metabolismo , Mitocôndrias/metabolismo , Proteases Dependentes de ATP/metabolismo , ATPases Associadas a Diversas Atividades Celulares , Apoptose , Complexo I de Transporte de Elétrons , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , GTP Fosfo-Hidrolases/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Membranas Mitocondriais/metabolismo , Proteínas Mitocondriais , NADH NADPH Oxirredutases/metabolismo , Peptídeo Hidrolases/metabolismo , Isoformas de Proteínas/metabolismo , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo
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