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1.
Nat Commun ; 10(1): 2576, 2019 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-31189900

RESUMO

Mitochondrial quality control is essential in highly structured cells such as neurons and muscles. In skeletal muscle the mitochondrial fission proteins are reduced in different physiopathological conditions including ageing sarcopenia, cancer cachexia and chemotherapy-induced muscle wasting. However, whether mitochondrial fission is essential for muscle homeostasis is still unclear. Here we show that muscle-specific loss of the pro-fission dynamin related protein (DRP) 1 induces muscle wasting and weakness. Constitutive Drp1 ablation in muscles reduces growth and causes animal death while inducible deletion results in atrophy and degeneration. Drp1 deficient mitochondria are morphologically bigger and functionally abnormal. The dysfunctional mitochondria signals to the nucleus to induce the ubiquitin-proteasome system and an Unfolded Protein Response while the change of mitochondrial volume results in an increase of mitochondrial Ca2+ uptake and myofiber death. Our findings reveal that morphology of mitochondrial network is critical for several biological processes that control nuclear programs and Ca2+ handling.


Assuntos
Dinaminas/metabolismo , Mitocôndrias Musculares/patologia , Dinâmica Mitocondrial/fisiologia , Miopatias Mitocondriais/patologia , Músculo Esquelético/patologia , Animais , Cálcio/metabolismo , Núcleo Celular/metabolismo , Modelos Animais de Doenças , Dinaminas/genética , Homeostase/fisiologia , Humanos , Camundongos , Camundongos Knockout , Miopatias Mitocondriais/genética , Miopatias Mitocondriais/mortalidade , Músculo Esquelético/citologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteólise , Ubiquitinas/metabolismo , Resposta a Proteínas não Dobradas/fisiologia
2.
Toxicon ; 166: 46-55, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31102596

RESUMO

'Go Slow myopathy' (GSM) is a suspected toxic myopathy in dogs that primarily occurs in the North Island of New Zealand, and affected dogs usually have a history of consuming meat, offal or bones from wild pigs (including previously frozen and/or cooked meat). Previous epidemiological and pathological studies on GSM have demonstrated that changes in mitochondrial structure and function are most likely caused by an environmental toxin that dogs are exposed to through the ingestion of wild pig. The disease has clinical, histological and biochemical similarities to poisoning in people and animals from the plant Ageratina altissima (white snakeroot). Aqueous and lipid extracts were prepared from liver samples of 24 clinically normal dogs and 15 dogs with GSM for untargeted liquid chromatography-mass spectrometry. Group-wise comparisons of mass spectral data revealed 38 features that were significantly different (FDR<0.05) between normal dogs and those with GSM in aqueous extracts, and 316 significantly different features in lipid extracts. No definitive cause of the myopathy was identified, but alkaloids derived from several plant species were among the possible identities of features that were more abundant in liver samples from affected dogs compared to normal dogs. Mass spectral data also revealed that dogs with GSM have reduced hepatic phospholipid and sphingolipid concentrations relative to normal dogs. In addition, affected dogs had changes in the abundance of kynurenic acid, various dicarboxylic acids and N-acetylated branch chain amino acids, suggestive of mitochondrial dysfunction.


Assuntos
Doenças do Cão/induzido quimicamente , Metaboloma , Miopatias Mitocondriais/veterinária , Intoxicação por Plantas/veterinária , Alcaloides/isolamento & purificação , Animais , Cromatografia Líquida/veterinária , Doenças do Cão/metabolismo , Cães , Fígado/metabolismo , Espectrometria de Massas/veterinária , Miopatias Mitocondriais/patologia , Nova Zelândia , Intoxicação por Plantas/diagnóstico
3.
Neuropathology ; 39(2): 162-167, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30847961

RESUMO

Oral nucleoside analogs (NAs) reduce hepatitis B virus (HBV) replication by inhibiting HBV DNA polymerase. However, NAs can also affect human mitochondrial DNA (mtDNA) polymerase, which can lead to mtDNA depletion (quantitative abnormality). Indeed, several mitochondrial myopathy cases have been reported in which a reduced mtDNA copy number was induced by oral NAs for hepatitis B. Herein, we report a case of toxic myopathy with multiple mtDNA deletions (qualitative abnormality) associated with long-term use of NAs for hepatitis B. A 68-year-old woman, who underwent long-term treatment with lamivudine and adefovir for chronic hepatitis B, developed proximal muscle weakness in the four extremities. Neurological examination showed mild proximal muscle weakness and atrophy in the four extremities. Upon admission to our hospital, her blood lactate/pyruvate ratio during an aerobic exercise test was elevated. Myogenic patterns were observed in lower limb muscles on electromyographic examination. Muscle magnetic resonance imaging revealed diffuse atrophy of proximal muscles in the four extremities with no signal changes. A biopsy from the biceps brachii muscle showed an abnormally large variation in fiber size, scattered muscle fibers with decreased cytochrome c oxidase activity, and ragged-red fibers. Analysis of mtDNA from skeletal muscle revealed no decrease in copy number but increased incidence of multiple deletions, including a deletion of 4977 base pairs (known as the common deletion) reflecting oxidative stress-induced mtDNA damage. This case study indicates that long-term oral antiviral therapy for hepatitis B can induce chronic oxidative damage to mtDNA resulting in qualitative mtDNA abnormalities and toxic myopathy.


Assuntos
Antivirais/efeitos adversos , Hepatite B Crônica/tratamento farmacológico , Miopatias Mitocondriais/induzido quimicamente , Miopatias Mitocondriais/patologia , Adenina/efeitos adversos , Adenina/análogos & derivados , Administração Oral , Idoso , DNA Mitocondrial , Feminino , Deleção de Genes , Hepatite B Crônica/complicações , Humanos , Lamivudina/efeitos adversos , Miopatias Mitocondriais/complicações , Miopatias Mitocondriais/genética , Músculo Esquelético/patologia , Organofosfonatos/efeitos adversos
4.
Skelet Muscle ; 9(1): 5, 2019 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-30791960

RESUMO

BACKGROUND: Group I Paks are serine/threonine kinases that function as major effectors of the small GTPases Rac1 and Cdc42, and they regulate cytoskeletal dynamics, cell polarity, and transcription. We previously demonstrated that Pak1 and Pak2 function redundantly to promote skeletal myoblast differentiation during postnatal development and regeneration in mice. However, the roles of Pak1 and Pak2 in adult muscle homeostasis are unknown. Choline kinase ß (Chk ß) is important for adult muscle homeostasis, as autosomal recessive mutations in CHKß are associated with two human muscle diseases, megaconial congenital muscular dystrophy and proximal myopathy with focal depletion of mitochondria. METHODS: We analyzed mice conditionally lacking Pak1 and Pak2 in the skeletal muscle lineage (double knockout (dKO) mice) over 1 year of age. Muscle integrity in dKO mice was assessed with histological stains, immunofluorescence, electron microscopy, and western blotting. Assays for mitochondrial respiratory complex function were performed, as was mass spectrometric quantification of products of choline kinase. Mice and cultured myoblasts deficient for choline kinase ß (Chk ß) were analyzed for Pak1/2 phosphorylation. RESULTS: dKO mice developed an age-related myopathy. By 10 months of age, dKO mouse muscles displayed centrally-nucleated myofibers, fibrosis, and signs of degeneration. Disease severity occurred in a rostrocaudal gradient, hindlimbs more strongly affected than forelimbs. A distinctive feature of this myopathy was elongated and branched intermyofibrillar (megaconial) mitochondria, accompanied by focal mitochondrial depletion in the central region of the fiber. dKO muscles showed reduced mitochondrial respiratory complex I and II activity. These phenotypes resemble those of rmd mice, which lack Chkß and are a model for human diseases associated with CHKß deficiency. Pak1/2 and Chkß activities were not interdependent in mouse skeletal muscle, suggesting a more complex relationship in regulation of mitochondria and muscle homeostasis. CONCLUSIONS: Conditional loss of Pak1 and Pak2 in mice resulted in an age-dependent myopathy with similarity to mice and humans with CHKß deficiency. Protein kinases are major regulators of most biological processes but few have been implicated in muscle maintenance or disease. Pak1/Pak2 dKO mice offer new insights into these processes.


Assuntos
Miopatias Mitocondriais/metabolismo , Músculo Esquelético/metabolismo , Quinases Ativadas por p21/metabolismo , Animais , Colina Quinase/metabolismo , Feminino , Masculino , Camundongos Knockout , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Miopatias Mitocondriais/genética , Miopatias Mitocondriais/patologia , Proteínas Mitocondriais/metabolismo , Músculo Esquelético/ultraestrutura , Quinases Ativadas por p21/genética
5.
Am J Kidney Dis ; 73(2): 273-277, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30309714

RESUMO

In human kidney disease, mitochondrial ultrastructural damage has long been recognized. Although the extent to which such mitochondrial changes contribute to human kidney disease is uncertain, experimental studies clearly demonstrate that mitochondrial damage can instigate pathogenetic processes that drive ongoing kidney disease. Clinical credence for this experimentally based hypothesis is provided by the development of kidney disease in patients with primary mitochondrial disorders. In this regard, substantial interest surrounds the occurrence of kidney disease in primary mitochondrial cytopathies, a heterogeneous group of conditions in which mutations in mitochondrial DNA (mtDNA) or nuclear DNA impair the functionality of components of the mitochondrial respiratory chain. We describe a novel mtDNA mutation in a patient who developed chronic kidney disease. The patient exhibited mitochondrial abnormalities in both muscle and kidney, chronic tubulointerstitial changes, and recurrent episodes of rhabdomyolysis. We outline mechanisms that may underlie the occurrence of chronic kidney disease in the setting of this novel mtDNA mutation. We also underscore the need to consider in relevant kidney diseases the presence of an underlying mitochondrial cytopathy because the latter more commonly exists than is generally recognized.


Assuntos
DNA Mitocondrial/genética , Síndrome de Kearns-Sayre/genética , Miopatias Mitocondriais/genética , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Rabdomiólise/genética , Centros Médicos Acadêmicos , Adulto , Biópsia por Agulha , Análise Mutacional de DNA , Diagnóstico Diferencial , Seguimentos , Humanos , Imuno-Histoquímica , Síndrome de Kearns-Sayre/patologia , Masculino , Miopatias Mitocondriais/patologia , Doenças Raras , Rabdomiólise/patologia , Medição de Risco
6.
Retin Cases Brief Rep ; 13(3): 279-282, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-28301411

RESUMO

PURPOSE: To report the retinal phenotype of a rare case of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)/trifunctional protein (TFP) deficiency diagnosed in his late 40s with ocular findings of diffuse chorioretinal atrophy and bilateral retinoschisis. METHODS: An acylcarnitine profile assay revealed LCHAD/TFP deficiency in a 45-year-old man with a history of high myopia, bilateral decreased vision, episodic rhabdomyolysis, and peripheral neuropathy. Ocular findings were evaluated with spectral domain optical coherence tomography (Spectralis OCT; Heidelberg Engineering, Heidelberg, Germany) and color fundus photography. RESULTS: Spectral domain optical coherence tomography revealed severe bilateral macular retinoschisis. Subretinal fibrosis was noted in the left temporal macula with an associated lamellar macular hole. Fundus photographs demonstrated diffuse, symmetric chorioretinal atrophy characteristic of end-stage retinopathy, as previously reported in younger patients. Myopic staphylomas were evident in the posterior pole of both eyes. A trial of topical dorzolamide for 3 months resulted in no change in the retinal profile. CONCLUSION: We report the retinal phenotype of a patient with LCHAD/TFP deficiency diagnosed later in life. To date, this is the oldest patient reported with LCHAD/TFP-associated retinopathy. Macular retinoschisis may represent a feature of the end-stage retinopathy due to the progressive myopia. The diagnosis of LCHAD/TFP deficiency should be considered in adult patients with a history rhabdomyolysis, neuropathy, and retinopathy, as they would not have undergone routine newborn screening before the late 90s.


Assuntos
Cardiomiopatias/patologia , Doenças da Coroide/patologia , Erros Inatos do Metabolismo Lipídico/patologia , 3-Hidroxiacil-CoA Desidrogenase de Cadeia Longa/deficiência , Miopatias Mitocondriais/patologia , Proteína Mitocondrial Trifuncional/deficiência , Doenças do Sistema Nervoso/patologia , Doenças Retinianas/patologia , Rabdomiólise/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Retinosquise/patologia
7.
Hum Mol Genet ; 27(23): 4135-4144, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30452684

RESUMO

Protein import into mitochondria is facilitated by translocases within the outer and the inner mitochondrial membranes that are dedicated to a highly specific subset of client proteins. The mitochondrial carrier translocase (TIM22 complex) inserts multispanning proteins, such as mitochondrial metabolite carriers and translocase subunits (TIM23, TIM17A/B and TIM22), into the inner mitochondrial membrane. Both types of substrates are essential for mitochondrial metabolic function and biogenesis. Here, we report on a subject, diagnosed at 1.5 years, with a neuromuscular presentation, comprising hypotonia, gastroesophageal reflux disease and persistently elevated serum and Cerebrospinal fluid lactate (CSF). Patient fibroblasts displayed reduced oxidative capacity and altered mitochondrial morphology. Using trans-mitochondrial cybrid cell lines, we excluded a candidate variant in mitochondrial DNA as causative of these effects. Whole-exome sequencing identified compound heterozygous variants in the TIM22 gene (NM_013337), resulting in premature truncation in one allele (p.Tyr25Ter) and a point mutation in a conserved residue (p.Val33Leu), within the intermembrane space region, of the TIM22 protein in the second allele. Although mRNA transcripts of TIM22 were elevated, biochemical analyses revealed lower levels of TIM22 protein and an even greater deficiency of TIM22 complex formation. In agreement with a defect in carrier translocase function, carrier protein amounts in the inner membrane were found to be reduced. This is the first report of pathogenic variants in the TIM22 pore-forming subunit of the carrier translocase affecting the biogenesis of inner mitochondrial membrane proteins critical for metabolite exchange.


Assuntos
Proteínas de Transporte/genética , Mitocôndrias/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Miopatias Mitocondriais/genética , Criança , DNA Mitocondrial/genética , Feminino , Fibroblastos/metabolismo , Predisposição Genética para Doença , Humanos , Ácido Láctico/líquido cefalorraquidiano , Proteínas de Membrana Transportadoras/genética , Mitocôndrias/patologia , Membranas Mitocondriais/metabolismo , Membranas Mitocondriais/patologia , Miopatias Mitocondriais/líquido cefalorraquidiano , Miopatias Mitocondriais/patologia , Mutação , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Sequenciamento Completo do Exoma
8.
EMBO Mol Med ; 10(11)2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30309855

RESUMO

The mTOR inhibitor rapamycin ameliorates the clinical and biochemical phenotype of mouse, worm, and cellular models of mitochondrial disease, via an unclear mechanism. Here, we show that prolonged rapamycin treatment improved motor endurance, corrected morphological abnormalities of muscle, and increased cytochrome c oxidase (COX) activity of a muscle-specific Cox15 knockout mouse (Cox15 sm/sm ). Rapamycin treatment restored autophagic flux, which was impaired in naïve Cox15 sm/sm muscle, and reduced the number of damaged mitochondria, which accumulated in untreated Cox15 sm/sm mice. Conversely, rilmenidine, an mTORC1-independent autophagy inducer, was ineffective on the myopathic features of Cox15 sm/sm animals. This stark difference supports the idea that inhibition of mTORC1 by rapamycin has a key role in the improvement of the mitochondrial function in Cox15 sm/sm muscle. In contrast to rilmenidine, rapamycin treatment also activated lysosomal biogenesis in muscle. This effect was associated with increased nuclear localization of TFEB, a master regulator of lysosomal biogenesis, which is inhibited by mTORC1-dependent phosphorylation. We propose that the coordinated activation of autophagic flux and lysosomal biogenesis contribute to the effective clearance of dysfunctional mitochondria by rapamycin.


Assuntos
Autofagia , Lisossomos/metabolismo , Miopatias Mitocondriais/patologia , Biogênese de Organelas , Sirolimo/farmacologia , Animais , Autofagia/efeitos dos fármacos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Lisossomos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Miopatias Mitocondriais/metabolismo , Atividade Motora/efeitos dos fármacos , Músculos/efeitos dos fármacos , Músculos/patologia , Fenótipo , Rilmenidina/farmacologia , Serina-Treonina Quinases TOR/metabolismo
9.
Cell Metab ; 28(5): 764-775.e5, 2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30122554

RESUMO

Alternative oxidases (AOXs) bypass respiratory complexes III and IV by transferring electrons from coenzyme Q directly to O2. They have therefore been proposed as a potential therapeutic tool for mitochondrial diseases. We crossed the severely myopathic skeletal muscle-specific COX15 knockout (KO) mouse with an AOX-transgenic mouse. Surprisingly, the double KO-AOX mutants had decreased lifespan and a substantial worsening of the myopathy compared with KO alone. Decreased ROS production in KO-AOX versus KO mice led to impaired AMPK/PGC-1α signaling and PAX7/MYOD-dependent muscle regeneration, blunting compensatory responses. Importantly, the antioxidant N-acetylcysteine had a similar effect, decreasing the lifespan of KO mice. Our findings have major implications for understanding pathogenic mechanisms in mitochondrial diseases and for the design of therapies, highlighting the benefits of ROS signaling and the potential hazards of antioxidant treatment.


Assuntos
Miopatias Mitocondriais/metabolismo , Proteínas Mitocondriais/metabolismo , Oxirredutases/metabolismo , Proteínas de Plantas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Animais , Autofagia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miopatias Mitocondriais/genética , Miopatias Mitocondriais/patologia , Proteínas Mitocondriais/genética , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Biogênese de Organelas , Oxirredução , Oxirredutases/genética , Proteínas de Plantas/genética
10.
J Pathol ; 246(4): 427-432, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30146801

RESUMO

Inherited mitochondrial DNA (mtDNA) mutations cause mitochondrial disease, but mtDNA mutations also occur somatically and accumulate during ageing. Studies have shown that the mutation load of some inherited mtDNA mutations decreases over time in blood, suggesting selection against the mutation. However, it is unknown whether such selection occurs in other mitotic tissues, and where it occurs within the tissue. Gastrointestinal epithelium is a canonical mitotic tissue rapidly renewed by stem cells. Intestinal crypts (epithelium) undergo monoclonal conversion with a single stem cell taking over the niche and producing progeny. We show: (1) that there is a significantly lower mtDNA mutation load in the mitotic epithelium of the gastrointestinal tract when compared to the smooth muscle in the same tissue in patients with the pathogenic m.3243A>G and m.8344A>G mutations; (2) that there is considerable variation seen in individual crypts, suggesting changes in the stem cell population; (3) that this lower mutation load is reflected in the absence of a defect in oxidative phosphorylation in the epithelium. This suggests that there is selection against inherited mtDNA mutations in the gastrointestinal stem cells that is in marked contrast to the somatic mtDNA mutations that accumulate with age in epithelial stem cells leading to a biochemical defect. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Assuntos
DNA Mitocondrial/genética , Células Epiteliais/química , Mucosa Gástrica/química , Mucosa Intestinal/química , Mitocôndrias/genética , Miopatias Mitocondriais/genética , Mutação , Células-Tronco/química , Adulto , Estudos de Casos e Controles , Senescência Celular/genética , Células Epiteliais/patologia , Feminino , Mucosa Gástrica/patologia , Predisposição Genética para Doença , Hereditariedade , Humanos , Mucosa Intestinal/patologia , Pessoa de Meia-Idade , Mitocôndrias/patologia , Miopatias Mitocondriais/patologia , Mitose , Miócitos de Músculo Liso/química , Miócitos de Músculo Liso/patologia , Fosforilação Oxidativa , Linhagem , Fenótipo , RNA de Transferência de Leucina/genética , RNA de Transferência de Lisina/genética , Seleção Genética , Células-Tronco/patologia
11.
Top Magn Reson Imaging ; 27(4): 219-240, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30086109

RESUMO

Mitochondrial diseases are a complex and heterogeneous group of genetic disorders that occur as a result of either nuclear DNA or mitochondrial DNA pathogenic variants, leading to a decrease in oxidative phosphorylation and cellular energy (ATP) production. Increasing knowledge about molecular, biochemical, and genetic abnormalities related to mitochondrial dysfunction has expanded the neuroimaging phenotypes of mitochondrial disorders. As a consequence of this growing field, the imaging recognition patterns of mitochondrial cytopathies are continually evolving. In this review, we describe the main neuroimaging characteristics of pediatric mitochondrial diseases, ranging from classical to more recent and challenging features. Due to the increased knowledge about the imaging findings of mitochondrial cytopathies, the pediatric neuroradiologist plays a crucial role in the diagnosis and evaluation of these patients.


Assuntos
Encéfalo/diagnóstico por imagem , Síndrome de Kearns-Sayre/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Miopatias Mitocondriais/diagnóstico por imagem , Neuroimagem/métodos , Encéfalo/patologia , Humanos , Síndrome de Kearns-Sayre/patologia , Miopatias Mitocondriais/patologia
13.
Neurobiol Aging ; 66: 181.e1-181.e2, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29519717

RESUMO

Mutations in CHCHD2 and CHCHD10 were recently reported in a broad spectrum of neurodegenerative diseases, for example, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, or mitochondrial myopathy (MM). The aim of the study was to evaluate the prevalence of CHCHD2 and CHCHD10 mutations in Italian MM patients without mitochondrial DNA mutations. The coding regions of CHCHD2 and CHCHD10 were sequenced in 62 MM patients. None of the patients showed CHCHD2 mutations, whereas 1 sporadic MM patient carried a homozygous Pro96Thr substitution in CHCHD10. Muscle biopsy of this patient showed intracellular glycogen accumulation with cytochrome c oxidase negative and ragged red fibers. Our study suggests that the homozygous Pro96Thr mutation in CHCHD10 might be pathogenic but does not support a major role for CHCHD2 in MM pathogenesis.


Assuntos
Estudos de Associação Genética , Miopatias Mitocondriais/genética , Proteínas Mitocondriais/genética , Mutação , Fatores de Transcrição/genética , Estudos de Coortes , Complexo IV da Cadeia de Transporte de Elétrons , Glicogênio/metabolismo , Humanos , Itália , Miopatias Mitocondriais/metabolismo , Miopatias Mitocondriais/patologia , Músculos/metabolismo , Músculos/patologia
15.
Clin Genet ; 93(5): 1097-1102, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29327420

RESUMO

SLC25A42 gene encodes an inner mitochondrial membrane protein that imports Coenzyme A into the mitochondrial matrix. A mutation in this gene was recently reported in a subject born to consanguineous parents who presented with mitochondrial myopathy with muscle weakness and lactic acidosis. In this report, we present 12 additional individuals with the same founder mutation who presented with variable manifestations ranging from asymptomatic lactic acidosis to a severe phenotype characterized by developmental regression and epilepsy. Our report confirms the link between SLC25A42 and mitochondrial disease in humans, and suggests that pathogenic variants in SLC25A42 should be interpreted with the understanding that the associated phenotype may be highly variable.


Assuntos
Acidose Láctica/genética , Encefalomiopatias Mitocondriais/genética , Miopatias Mitocondriais/genética , Proteínas de Transporte de Nucleotídeos/genética , Acidose Láctica/patologia , Adolescente , Adulto , Criança , Pré-Escolar , DNA Mitocondrial , Feminino , Humanos , Lactente , Masculino , Mitocôndrias/genética , Mitocôndrias/patologia , Encefalomiopatias Mitocondriais/complicações , Encefalomiopatias Mitocondriais/patologia , Miopatias Mitocondriais/patologia , Linhagem , Fenótipo , Mutação Puntual , Adulto Jovem
16.
Mitochondrion ; 39: 26-29, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28823815

RESUMO

We report the clinical, morphological and molecular features of two patients with autosomal recessive SLC25A4 (ANT1) gene mutations. Furthermore, all previously published cases are reviewed to identify valuable features for future diagnosis. Patients present a common phenotype with exercise intolerance, hyperlactatemia, and hypertrophic cardiomyopathy. Muscle biopsies show wide sub-sarcolemmal mitochondrial aggregates, and increased activities of all respiratory chain complexes. The phenotype of recessive SLC25A4 (ANT1) mutations although rare, is homogenous and easily recognizable and could help orientate the molecular analysis in adults with exercise intolerance associated with hyperlactatemia.


Assuntos
Translocador 1 do Nucleotídeo Adenina/genética , Cardiomiopatias/etiologia , Cardiomiopatias/patologia , Hiperlactatemia/etiologia , Hiperlactatemia/patologia , Miopatias Mitocondriais/complicações , Miopatias Mitocondriais/patologia , Adulto , Exercício , Feminino , Genes Recessivos , Humanos , Pessoa de Meia-Idade , Mitocôndrias/patologia , Miopatias Mitocondriais/genética , Músculos/patologia , Mutação
17.
Neuromuscul Disord ; 28(2): 137-143, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29174468

RESUMO

We report on two novel mtDNA mutations in patients affected with mitochondrial myopathy. The first patient, a 44-year-old woman, had bilateral eyelid ptosis and the m.8305C>T mutation in the MTTK gene. The second patient, a 56-year-old man, had four-limb muscle weakness and the MTTM gene m.4440G>A mutation. Muscle biopsies in both patients showed ragged red fibers and numerous COX-negative fibers as well as a combined defect of complex I, III and IV activities. The two mutations were heteroplasmic and detected only in muscle tissue, with a higher mutation load in COX-negative fibers. Additionally, both mutations occurred in highly conserved mt-tRNA sites, and were not found by an in silico search in 30,589 human mtDNA sequences. Our report further expands the mutational and phenotypic spectrum of diseases associated with mutations in mitochondrial tRNA genes and reinforces the notion that mutations in mitochondrial tRNAs represent hot spots for mitochondrial myopathies in adults.


Assuntos
DNA Mitocondrial , Miopatias Mitocondriais/genética , Mutação Puntual , RNA de Transferência de Lisina/genética , RNA de Transferência de Metionina/genética , Adulto , Feminino , Genes Mitocondriais , Humanos , Masculino , Pessoa de Meia-Idade , Miopatias Mitocondriais/metabolismo , Miopatias Mitocondriais/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Fenótipo
18.
BMC Musculoskelet Disord ; 18(1): 419, 2017 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-29052516

RESUMO

BACKGROUND: Pure exercise intolerance associated with exclusive affection of skeletal muscle is a very rare phenotype of patients with mitochondrial myopathy. Moreover, the exercise intolerance in these rare patients is yet not well explored, as most of known cases have not been assessed by objective testing, but only by interview. We report a patient with a mitochondrial DNA (mtDNA) mutation that gives rise to an exclusive myopathy associated with exercise intolerance and ophthalmoplegia. We quantified the patient's exercise intolerance through detailed exercise testing. CASE PRESENTATION: A 39-year-old man presented with exercise intolerance and chronic progressive external ophthalmoplegia. Sequencing of the entire mtDNA identified a m.12,294G > A mutation in the MT-TL2 gene. The mutation was heteroplasmic in skeletal muscle (75%) while undetectable in blood, urinary sediment, and buccal mucosa as well as in tissues from the patient's mother. The mutation affected a highly conserved site in the anticodon stem of the mitochondrial transfer RNA Leucine (CUN) molecule and lead to a severe combined respiratory chain defect. Exercise physiological studies in the patient demonstrated a significantly reduced maximal oxygen uptake of 20.4 ml O2 × min-1 × kg-1 (about half of normal) as well as threefold elevated lactate/pyruvate ratios. CONCLUSION: The findings of our study support that the m.12,294G > A mutation is pathogenic. Likely, the mutation arose sporadically in early embryogenesis after differentiation of the mesoderm into muscle progenitor cells, leading to a pure myopathic phenotype.


Assuntos
DNA Mitocondrial/genética , Tolerância ao Exercício/genética , Miopatias Mitocondriais/genética , Oftalmoplegia/genética , Adulto , Transporte de Elétrons , Teste de Esforço , Humanos , Masculino , Miopatias Mitocondriais/complicações , Miopatias Mitocondriais/patologia , Mutação , Músculo Quadríceps/enzimologia , Músculo Quadríceps/patologia
19.
Ann Diagn Pathol ; 29: 41-45, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28807341

RESUMO

Ultrastructural evaluation of skin biopsies has been utilized for diagnosis of mitochondrial disease. This study investigates how frequently skin biopsies reveal mitochondrial abnormalities, correlates skin and muscle biopsy findings, and describes clinical diagnoses rendered following the evaluation. A retrospective review of surgical pathology reports from 1990 to 2015 identified skin biopsies examined by electron microscopy for suspected metabolic disease. A total of 630 biopsies were included from 615 patients. Of these patients, 178 also underwent a muscle biopsy. Of the 630 skin biopsies, 75 (12%) showed ultrastructural abnormalities and 34 (5%) specifically showed mitochondrial abnormalities including increased size (n=27), reduced or abnormal cristae (n=23), dense matrices (n=20), and increased number (n=8). Additional findings included lysosomal abnormalities (n=13), lipid accumulation (n=2) or glycogen accumulation (n=1). Of the 34 patients with mitochondrial abnormalities on skin biopsy, 20 also had muscle biopsies performed and nine showed abnormalities suggestive of a mitochondrial disorder including absent cytochrome oxidase staining (n=2), increased subsarcolemmal NADH, SDH, or cytochrome oxidase staining (n=1), or ultrastructural findings including large mitochondrial size (n=5), abnormal mitochondrial structure (n=5), and increased mitochondrial number (n=4). The most common presenting symptoms were intellectual disability (n=13), seizures (n=12), encephalopathy (n=9), and gastrointestinal disturbances (n=9). At last known follow-up, 12 patients had a definitive diagnosis of a mitochondrial disorder. One patient each had Complex I deficiency, Complex III deficiency, Charcot-Marie-Tooth disease, pyruvate dehydrogenase deficiency, and Phelan-McDermid syndrome. Our results suggest that skin biopsy sometimes yields diagnostic clues suggestive of a mitochondrial cytopathy in cases with a negative muscle biopsy.


Assuntos
Síndrome de Kearns-Sayre/patologia , Mitocôndrias/ultraestrutura , Miopatias Mitocondriais/patologia , Pele/patologia , Adolescente , Biópsia/métodos , Criança , Pré-Escolar , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Humanos , Masculino , Microscopia Eletrônica/métodos , Músculo Esquelético/patologia , Estudos Retrospectivos
20.
Cell Metab ; 26(2): 419-428.e5, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28768179

RESUMO

Mitochondrial dysfunction elicits various stress responses in different model systems, but how these responses relate to each other and contribute to mitochondrial disease has remained unclear. Mitochondrial myopathy (MM) is the most common manifestation of adult-onset mitochondrial disease and shows a multifaceted tissue-specific stress response: (1) transcriptional response, including metabolic cytokines FGF21 and GDF15; (2) remodeling of one-carbon metabolism; and (3) mitochondrial unfolded protein response. We show that these processes are part of one integrated mitochondrial stress response (ISRmt), which is controlled by mTORC1 in muscle. mTORC1 inhibition by rapamycin downregulated all components of ISRmt, improved all MM hallmarks, and reversed the progression of even late-stage MM, without inducing mitochondrial biogenesis. Our evidence suggests that (1) chronic upregulation of anabolic pathways contributes to MM progression, (2) long-term induction of ISRmt is not protective for muscle, and (3) rapamycin treatment trials should be considered for adult-type MM with raised FGF21.


Assuntos
Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Mitocôndrias Musculares/metabolismo , Miopatias Mitocondriais/metabolismo , Estresse Fisiológico , Animais , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Camundongos , Pessoa de Meia-Idade , Mitocôndrias Musculares/genética , Mitocôndrias Musculares/patologia , Miopatias Mitocondriais/genética , Miopatias Mitocondriais/patologia
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