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1.
Cell Rep ; 43(5): 114148, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38697100

RESUMO

Coenzyme Q (CoQ) deficiency syndrome is conventionally treated with limited efficacy using exogenous CoQ10. Poor outcomes result from low absorption and bioavailability of CoQ10 and the clinical heterogenicity of the disease. Here, we demonstrate that supplementation with 4-hydroxybenzoic acid (4HB), the precursor of the benzoquinone ring in the CoQ biosynthetic pathway, completely rescues multisystemic disease and perinatal lethality in a mouse model of CoQ deficiency. 4HB stimulates endogenous CoQ biosynthesis in tissues of Coq2 mutant mice, normalizing mitochondrial function and rescuing cardiac insufficiency, edema, and neurodevelopmental delay. In contrast, exogenous CoQ10 supplementation falls short in fully restoring the phenotype. The treatment is translatable to human use, as proven by in vitro studies in skin fibroblasts from patients with pathogenic variants in COQ2. The therapeutic approach extends to other disorders characterized by deficiencies in the production of 4HB and early steps of CoQ biosynthesis and instances of secondary CoQ deficiency.


Assuntos
Modelos Animais de Doenças , Doenças Mitocondriais , Parabenos , Ubiquinona , Animais , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/patologia , Doenças Mitocondriais/metabolismo , Parabenos/farmacologia , Ubiquinona/análogos & derivados , Ubiquinona/farmacologia , Ubiquinona/metabolismo , Ubiquinona/deficiência , Camundongos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Humanos , Fibroblastos/metabolismo , Fibroblastos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Debilidade Muscular/tratamento farmacológico , Debilidade Muscular/metabolismo , Debilidade Muscular/patologia , Ataxia/tratamento farmacológico , Ataxia/patologia , Ataxia/metabolismo
2.
Neurol Genet ; 9(2): e200058, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37090936

RESUMO

Background and Objectives: Coenzyme Q10 (CoQ10)-deficient cerebellar ataxia can be due to pathogenic variants in genes encoding for CoQ10 biosynthetic proteins or associated with defects in protein unrelated to its biosynthesis. Diagnosis is crucial because patients may respond favorably to CoQ10 supplementation. The aim of this study was to identify through whole-exome sequencing (WES) the pathogenic variants, and assess CoQ10 levels, in fibroblasts from patients with undiagnosed cerebellar ataxia referred to investigate CoQ10 deficiency. Methods: WES was performed on genomic DNA extracted from 16 patients. Sequencing data were filtered using a virtual panel of genes associated with CoQ10 deficiency and/or cerebellar ataxia. CoQ10 levels were measured by high-performance liquid chromatography in 14 patient-derived fibroblasts. Results: A definite genetic etiology was identified in 8 samples of 16 (diagnostic yield = 50%). The identified genetic causes were pathogenic variants of the genes COQ8A (ADCK3) (n = 3 samples), ATP1A3 (n = 2), PLA2G6 (n = 1), SPG7 (n = 1), and MFSD8 (n = 1). Five novel mutations were found (COQ8A n = 3, PLA2G6 n = 1, and MFSD8 n = 1). CoQ10 levels were significantly decreased in 3/14 fibroblast samples (21.4%), 1 carrying compound heterozygous COQ8A pathogenic variants, 1 harboring a homozygous pathogenic SPG7 variant, and 1 with an unknown molecular defect. Discussion: This work confirms the importance of COQ8A gene mutations as a frequent genetic cause of cerebellar ataxia and CoQ10 deficiency and suggests SPG7 mutations as a novel cause of secondary CoQ10 deficiency.

3.
Antioxidants (Basel) ; 11(4)2022 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-35453349

RESUMO

Coenzyme Q (CoQ) is a conserved polyprenylated lipid composed of a redox-active benzoquinone ring and a long polyisoprenyl tail that serves as a membrane anchor. CoQ biosynthesis involves multiple steps, including multiple modifications of the precursor ring 4-hydroxybenzoic acid. Mutations in the enzymes involved in CoQ biosynthesis pathway result in primary coenzyme Q deficiencies, mitochondrial disorders whose clinical heterogenicity reflects the multiple biological function of CoQ. Patients with these disorders do not always respond to CoQ supplementation, and CoQ analogs have not been successful as alternative approaches. Progress made in understanding the CoQ biosynthesis pathway and studies of supplementation with 4-hydroxybenzoic acid ring analogs have opened a new area in the field of primary CoQ deficiencies treatment. Here, we will review these studies, focusing on efficacy of the different 4-hydroxybenzoic acid ring analogs, models in which they have been tested, and their mechanisms of action. Understanding how these compounds ameliorate biochemical, molecular, and/or clinical phenotypes of CoQ deficiencies is important to develop the most rational treatment for CoQ deficient patients, depending on their molecular defects.

4.
Cell Rep ; 38(10): 110475, 2022 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-35263592

RESUMO

Mitochondrial cardiomyopathies are fatal diseases, with no effective treatment. Alterations of heart mitochondrial function activate the mitochondrial integrated stress response (ISRmt), a transcriptional program affecting cell metabolism, mitochondrial biogenesis, and proteostasis. In humans, mutations in CHCHD10, a mitochondrial protein with unknown function, were recently associated with dominant multi-system mitochondrial diseases, whose pathogenic mechanisms remain to be elucidated. Here, in CHCHD10 knockin mutant mice, we identify an extensive cardiac metabolic rewiring triggered by proteotoxic ISRmt. The stress response arises early on, before the onset of bioenergetic impairments, triggering a switch from oxidative to glycolytic metabolism, enhancement of transsulfuration and one carbon (1C) metabolism, and widespread metabolic imbalance. In parallel, increased NADPH oxidases elicit antioxidant responses, leading to heme depletion. As the disease progresses, the adaptive metabolic stress response fails, resulting in fatal cardiomyopathy. Our findings suggest that early interventions to counteract metabolic imbalance could ameliorate mitochondrial cardiomyopathy associated with proteotoxic ISRmt.


Assuntos
Cardiomiopatias , Doenças Mitocondriais , Animais , Cardiomiopatias/patologia , Modelos Animais de Doenças , Camundongos , Mitocôndrias/metabolismo , Doenças Mitocondriais/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo
5.
Nat Commun ; 12(1): 5203, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471141

RESUMO

Aurora kinase A (AURKA) has emerged as a drug target for glioblastoma (GBM). However, resistance to therapy remains a critical issue. By integration of transcriptome, chromatin immunoprecipitation sequencing (CHIP-seq), Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq), proteomic and metabolite screening followed by carbon tracing and extracellular flux analyses we show that genetic and pharmacological AURKA inhibition elicits metabolic reprogramming mediated by inhibition of MYC targets and concomitant activation of Peroxisome Proliferator Activated Receptor Alpha (PPARA) signaling. While glycolysis is suppressed by AURKA inhibition, we note an increase in the oxygen consumption rate fueled by enhanced fatty acid oxidation (FAO), which was accompanied by an increase of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α). Combining AURKA inhibitors with inhibitors of FAO extends overall survival in orthotopic GBM PDX models. Taken together, these data suggest that simultaneous targeting of oxidative metabolism and AURKAi might be a potential novel therapy against recalcitrant malignancies.


Assuntos
Aurora Quinase A/genética , Aurora Quinase A/metabolismo , Glioblastoma/genética , Glioblastoma/metabolismo , Efeito Warburg em Oncologia , Linhagem Celular Tumoral , Proliferação de Células , Ácidos Graxos/metabolismo , Glicólise/efeitos dos fármacos , Humanos , PPAR alfa/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteômica , Transdução de Sinais/efeitos dos fármacos , Transcriptoma , Efeito Warburg em Oncologia/efeitos dos fármacos
6.
Antioxidants (Basel) ; 10(4)2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33810539

RESUMO

Coenzyme Q10 (CoQ10) is classically viewed as an important endogenous antioxidant and key component of the mitochondrial respiratory chain. For this second function, CoQ molecules seem to be dynamically segmented in a pool attached and engulfed by the super-complexes I + III, and a free pool available for complex II or any other mitochondrial enzyme that uses CoQ as a cofactor. This CoQ-free pool is, therefore, used by enzymes that link the mitochondrial respiratory chain to other pathways, such as the pyrimidine de novo biosynthesis, fatty acid ß-oxidation and amino acid catabolism, glycine metabolism, proline, glyoxylate and arginine metabolism, and sulfide oxidation metabolism. Some of these mitochondrial pathways are also connected to metabolic pathways in other compartments of the cell and, consequently, CoQ could indirectly modulate metabolic pathways located outside the mitochondria. Thus, we review the most relevant findings in all these metabolic functions of CoQ and their relations with the pathomechanisms of some metabolic diseases, highlighting some future perspectives and potential therapeutic implications.

7.
J Clin Invest ; 131(5)2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33444290

RESUMO

Mutations affecting mitochondrial coenzyme Q (CoQ) biosynthesis lead to kidney failure due to selective loss of podocytes, essential cells of the kidney filter. Curiously, neighboring tubular epithelial cells are spared early in disease despite higher mitochondrial content. We sought to illuminate noncanonical, cell-specific roles for CoQ, independently of the electron transport chain (ETC). Here, we demonstrate that CoQ depletion caused by Pdss2 enzyme deficiency in podocytes results in perturbations in polyunsaturated fatty acid (PUFA) metabolism and the Braf/Mapk pathway rather than ETC dysfunction. Single-nucleus RNA-Seq from kidneys of Pdss2kd/kd mice with nephrotic syndrome and global CoQ deficiency identified a podocyte-specific perturbation of the Braf/Mapk pathway. Treatment with GDC-0879, a Braf/Mapk-targeting compound, ameliorated kidney disease in Pdss2kd/kd mice. Mechanistic studies in Pdss2-depleted podocytes revealed a previously unknown perturbation in PUFA metabolism that was confirmed in vivo. Gpx4, an enzyme that protects against PUFA-mediated lipid peroxidation, was elevated in disease and restored after GDC-0879 treatment. We demonstrate broader human disease relevance by uncovering patterns of GPX4 and Braf/Mapk pathway gene expression in tissue from patients with kidney diseases. Our studies reveal ETC-independent roles for CoQ in podocytes and point to Braf/Mapk as a candidate pathway for the treatment of kidney diseases.


Assuntos
Ataxia/metabolismo , Indenos/farmacologia , Nefropatias/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Doenças Mitocondriais/metabolismo , Debilidade Muscular/metabolismo , Podócitos/metabolismo , Proteínas Proto-Oncogênicas B-raf/metabolismo , Pirazóis/farmacologia , Ubiquinona/deficiência , Alquil e Aril Transferases/genética , Alquil e Aril Transferases/metabolismo , Animais , Ataxia/tratamento farmacológico , Ataxia/genética , Ataxia/patologia , Sistemas de Liberação de Medicamentos , Células HEK293 , Humanos , Nefropatias/tratamento farmacológico , Nefropatias/genética , Nefropatias/patologia , Peroxidação de Lipídeos/genética , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/genética , Doenças Mitocondriais/patologia , Debilidade Muscular/tratamento farmacológico , Debilidade Muscular/genética , Debilidade Muscular/patologia , Podócitos/patologia , Proteínas Proto-Oncogênicas B-raf/genética , RNA-Seq , Ubiquinona/genética , Ubiquinona/metabolismo
8.
J Adv Res ; 27: 79-84, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33318868

RESUMO

BACKGROUND: Mitochondrial disorders are genetic diseases for which therapy remains woefully inadequate. Therapy of these disorders is particularly challenging partially due to the heterogeneity and tissue-specificity of pathomechanisms involved in these disorders. Abnormalities in hydrogen sulfide (H2S) metabolism are emerging as novel mechanism in mitochondrial dysfunction. However, further studies are necessary to understand the effects, protective or detrimental, of these abnormalities, and their relevance, in mitochondrial diseases. AIM OF REVIEW: To review the recent evidences of derangement of the metabolism of H2S, at biosynthesis or oxidation levels, in mitochondrial dysfunction, focusing specifically on the alterations of H2S oxidation caused by primary Coenzyme Q (CoQ) deficiency. KEY SCIENTIFIC CONCEPTS OF REVIEW: Mitochondria play a key role in the regulation of H2S and GSH metabolism pathways. However, further studies are needed to understand the consequences of abnormalities of H2S and GSH synthesis on the oxidation pathway, and vice versa; and on the levels of H2S and GSH, their tissue-specific detrimental effects, and their role the role in mitochondrial diseases. Beside the known H2S pathways, additional, tissue-specific, enzymatic systems, involved in H2S production and elimination, might exist.

9.
J Inherit Metab Dis ; 44(2): 292-300, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33368420

RESUMO

At present, there is just one approved therapy for patients with mitochondrial diseases in Europe, another in Japan, and none in the United States. These facts reveal an important and significant unmet need for approved therapies for these debilitating and often fatal disorders. To fill this need, it is critical for clinicians and drug developers to work closely with regulatory agencies. In the United States, mitochondrial disease patients and clinicians, the United Mitochondrial Disease Foundation, and pharmaceutical industry members have engaged with the Food and Drug Administration to educate each other about these complex and heterogeneous diseases and about regulatory requirements to obtain approvals for novel therapies. Clinical development of therapies for rare diseases has been facilitated by the 1983 US Orphan Drug Act (ODA) and similar legislation in Japan and the European Union. Further legislation and regulatory guidance have expanded and refined regulatory flexibility. While regulatory and financial incentives of the ODA have augmented involvement of pharmaceutical companies, clinicians, with patient advocacy groups and industry, need to conduct natural history studies, develop clinical outcome measures, and identify potential supportive surrogate endpoints predictive of clinical benefit, which together are critical foundations for clinical trials. Thus, the regulatory environment for novel therapeutic development is conducive and offers flexibility for mitochondrial diseases. Nevertheless, flexibility does not mean lower standards, as well-controlled rigorous clinical trials of high quality are still required to establish the efficacy of potential therapies and to obtain regulatory agency approvals for their commercial use. This process is illustrated through the authors' ongoing efforts to develop therapy for thymidine kinase 2 deficiency.


Assuntos
Doenças Mitocondriais/tratamento farmacológico , Produção de Droga sem Interesse Comercial/legislação & jurisprudência , Aprovação de Drogas , Humanos , Doenças Raras/tratamento farmacológico , Estados Unidos , United States Food and Drug Administration
10.
Hum Mol Genet ; 29(19): 3296-3311, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-32975579

RESUMO

Abnormalities of one carbon, glutathione and sulfide metabolisms have recently emerged as novel pathomechanisms in diseases with mitochondrial dysfunction. However, the mechanisms underlying these abnormalities are not clear. Also, we recently showed that sulfide oxidation is impaired in Coenzyme Q10 (CoQ10) deficiency. This finding leads us to hypothesize that the therapeutic effects of CoQ10, frequently administered to patients with primary or secondary mitochondrial dysfunction, might be due to its function as cofactor for sulfide:quinone oxidoreductase (SQOR), the first enzyme in the sulfide oxidation pathway. Here, using biased and unbiased approaches, we show that supraphysiological levels of CoQ10 induces an increase in the expression of SQOR in skin fibroblasts from control subjects and patients with mutations in Complex I subunits genes or CoQ biosynthetic genes. This increase of SQOR induces the downregulation of the cystathionine ß-synthase and cystathionine γ-lyase, two enzymes of the transsulfuration pathway, the subsequent downregulation of serine biosynthesis and the adaptation of other sulfide linked pathways, such as folate cycle, nucleotides metabolism and glutathione system. These metabolic changes are independent of the presence of sulfur aminoacids, are confirmed in mouse models, and are recapitulated by overexpression of SQOR, further proving that the metabolic effects of CoQ10 supplementation are mediated by the overexpression of SQOR. Our results contribute to a better understanding of how sulfide metabolism is integrated in one carbon metabolism and may explain some of the benefits of CoQ10 supplementation observed in mitochondrial diseases.


Assuntos
Ataxia/patologia , Carbono/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Mitocôndrias/patologia , Doenças Mitocondriais/patologia , Debilidade Muscular/patologia , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/metabolismo , Sulfetos/metabolismo , Ubiquinona/análogos & derivados , Ubiquinona/deficiência , Animais , Ataxia/genética , Ataxia/metabolismo , Transporte de Elétrons , Complexo I de Transporte de Elétrons/genética , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Glutationa/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Debilidade Muscular/genética , Debilidade Muscular/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/genética , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia , Transcriptoma , Ubiquinona/genética , Ubiquinona/metabolismo , Ubiquinona/farmacologia , Vitaminas/farmacologia
11.
Cells ; 9(7)2020 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664214

RESUMO

The heterogeneity of glioblastomas, the most common primary malignant brain tumor, remains a significant challenge for the treatment of these devastating tumors. Therefore, novel combination treatments are warranted. Here, we showed that the combined inhibition of TRAP1 by gamitrinib and histone deacetylases (HDAC1/HDAC2) through romidepsin or panobinostat caused synergistic growth reduction of established and patient-derived xenograft (PDX) glioblastoma cells. This was accompanied by enhanced cell death with features of apoptosis and activation of caspases. The combination treatment modulated the levels of pro- and anti-apoptotic Bcl-2 family members, including BIM and Noxa, Mcl-1, Bcl-2 and Bcl-xL. Silencing of Noxa, BAK and BAX attenuated the effects of the combination treatment. At the metabolic level, the combination treatment led to an enhanced reduction of oxygen consumption rate and elicited an unfolded stress response. Finally, we tested whether the combination treatment of gamitrinib and panobinostat exerted therapeutic efficacy in PDX models of glioblastoma (GBM) in mice. While single treatments led to mild to moderate reduction in tumor growth, the combination treatment suppressed tumor growth significantly stronger than single treatments without induction of toxicity. Taken together, we have provided evidence that simultaneous targeting of TRAP1 and HDAC1/2 is efficacious to reduce tumor growth in model systems of glioblastoma.


Assuntos
Antineoplásicos/uso terapêutico , Glioblastoma/tratamento farmacológico , Proteínas de Choque Térmico HSP90/metabolismo , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/metabolismo , Inibidores de Histona Desacetilases/uso terapêutico , Animais , Western Blotting , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Imunoprecipitação da Cromatina , Transporte de Elétrons/efeitos dos fármacos , Citometria de Fluxo , Glioblastoma/metabolismo , Humanos , Marcação In Situ das Extremidades Cortadas , Camundongos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Ensaios Antitumorais Modelo de Xenoenxerto
12.
J Clin Invest ; 130(7): 3699-3716, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32315286

RESUMO

The Warburg effect is a tumor-related phenomenon that could potentially be targeted therapeutically. Here, we showed that glioblastoma (GBM) cultures and patients' tumors harbored super-enhancers in several genes related to the Warburg effect. By conducting a transcriptome analysis followed by ChIP-Seq coupled with a comprehensive metabolite analysis in GBM models, we found that FDA-approved global (panobinostat, vorinostat) and selective (romidepsin) histone deacetylase (HDAC) inhibitors elicited metabolic reprogramming in concert with disruption of several Warburg effect-related super-enhancers. Extracellular flux and carbon-tracing analyses revealed that HDAC inhibitors blunted glycolysis in a c-Myc-dependent manner and lowered ATP levels. This resulted in the engagement of oxidative phosphorylation (OXPHOS) driven by elevated fatty acid oxidation (FAO), rendering GBM cells dependent on these pathways. Mechanistically, interference with HDAC1/-2 elicited a suppression of c-Myc protein levels and a concomitant increase in 2 transcriptional drivers of oxidative metabolism, PGC1α and PPARD, suggesting an inverse relationship. Rescue and ChIP experiments indicated that c-Myc bound to the promoter regions of PGC1α and PPARD to counteract their upregulation driven by HDAC1/-2 inhibition. Finally, we demonstrated that combination treatment with HDAC and FAO inhibitors extended animal survival in patient-derived xenograft model systems in vivo more potently than single treatments in the absence of toxicity.


Assuntos
Reprogramação Celular/efeitos dos fármacos , Glioblastoma , Glicólise/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Fosforilação Oxidativa/efeitos dos fármacos , Animais , Ácidos Graxos/metabolismo , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Glioblastoma/patologia , Células HCT116 , Histona Desacetilase 1/antagonistas & inibidores , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/antagonistas & inibidores , Histona Desacetilase 2/metabolismo , Humanos , Camundongos , PPAR delta/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Elementos de Resposta
13.
FASEB J ; 34(6): 7404-7426, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32307754

RESUMO

Fragile X syndrome (FXS) is the leading known inherited intellectual disability and the most common genetic cause of autism. The full mutation results in transcriptional silencing of the Fmr1 gene and loss of fragile X mental retardation protein (FMRP) expression. Defects in neuroenergetic capacity are known to cause a variety of neurodevelopmental disorders. Thus, we explored the integrity of forebrain mitochondria in Fmr1 knockout mice during the peak of synaptogenesis. We found inefficient thermogenic respiration due to futile proton leak in Fmr1 KO mitochondria caused by coenzyme Q (CoQ) deficiency and an open cyclosporine-sensitive channel. Repletion of mitochondrial CoQ within the Fmr1 KO forebrain closed the channel, blocked the pathological proton leak, restored rates of protein synthesis during synaptogenesis, and normalized the key phenotypic features later in life. The findings demonstrate that FMRP deficiency results in inefficient oxidative phosphorylation during the neurodevelopment and suggest that dysfunctional mitochondria may contribute to the FXS phenotype.


Assuntos
Respiração Celular/fisiologia , Síndrome do Cromossomo X Frágil/metabolismo , Síndrome do Cromossomo X Frágil/patologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Termogênese/fisiologia , Animais , Transtorno Autístico/metabolismo , Transtorno Autístico/patologia , Modelos Animais de Doenças , Feminino , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Masculino , Camundongos , Camundongos Knockout , Neurogênese/fisiologia , Prótons
14.
J Transl Genet Genom ; 4: 22-35, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33426503

RESUMO

Primary coenzyme Q10 (CoQ10) deficiency encompasses a subset of mitochondrial diseases caused by mutations affecting proteins involved in the CoQ10 biosynthetic pathway. One of the most frequent clinical syndromes associated with primary CoQ10 deficiency is the severe infantile multisystemic form, which, until recently, was underdiagnosed. In the last few years, the availability of genetic screening through whole exome sequencing and whole genome sequencing has enabled molecular diagnosis in a growing number of patients with this syndrome and has revealed new disease phenotypes and molecular defects in CoQ10 biosynthetic pathway genes. Early genetic screening can rapidly and non-invasively diagnose primary CoQ10 deficiencies. Early diagnosis is particularly important in cases of CoQ10 deficient steroid-resistant nephrotic syndrome, which frequently improves with treatment. In contrast, the infantile multisystemic forms of CoQ10 deficiency, particularly when manifesting with encephalopathy, present therapeutic challenges, due to poor responses to CoQ10 supplementation. Administration of CoQ10 biosynthetic intermediate compounds is a promising alternative to CoQ10; however, further pre-clinical studies are needed to establish their safety and efficacy, as well as to elucidate the mechanism of actions of the intermediates. Here, we review the molecular defects causes of the multisystemic infantile phenotype of primary CoQ10 deficiency, genotype-phenotype correlations, and recent therapeutic advances.

15.
Cancer Res ; 80(1): 30-43, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31694905

RESUMO

The receptor kinase c-MET has emerged as a target for glioblastoma therapy. However, treatment resistance emerges inevitably. Here, we performed global metabolite screening with metabolite set enrichment coupled with transcriptome and gene set enrichment analysis and proteomic screening, and identified substantial reprogramming of tumor metabolism involving oxidative phosphorylation and fatty acid oxidation (FAO) with substantial accumulation of acyl-carnitines accompanied by an increase of PGC1α in response to genetic (shRNA and CRISPR/Cas9) and pharmacologic (crizotinib) inhibition of c-MET. Extracellular flux and carbon tracing analyses (U-13C-glucose, U-13C-glutamine, and U-13C-palmitic acid) demonstrated enhanced oxidative metabolism, which was driven by FAO and supported by increased anaplerosis of glucose carbons. These findings were observed in concert with increased number and fusion of mitochondria and production of reactive oxygen species. Genetic interference with PGC1α rescued this oxidative phenotype driven by c-MET inhibition. Silencing and chromatin immunoprecipitation experiments demonstrated that cAMP response elements binding protein regulates the expression of PGC1α in the context of c-MET inhibition. Interference with both oxidative phosphorylation (metformin, oligomycin) and ß-oxidation of fatty acids (etomoxir) enhanced the antitumor efficacy of c-MET inhibition. Synergistic cell death was observed with c-MET inhibition and gamitrinib treatment. In patient-derived xenograft models, combination treatments of crizotinib and etomoxir, and crizotinib and gamitrinib were significantly more efficacious than single treatments and did not induce toxicity. Collectively, we have unraveled the mechanistic underpinnings of c-MET inhibition and identified novel combination therapies that may enhance its therapeutic efficacy. SIGNIFICANCE: c-MET inhibition causes profound metabolic reprogramming that can be targeted by drug combination therapies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Carnitina/análogos & derivados , Carnitina/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Respiração Celular/efeitos dos fármacos , Crizotinibe/farmacologia , Crizotinibe/uso terapêutico , Sinergismo Farmacológico , Compostos de Epóxi/farmacologia , Compostos de Epóxi/uso terapêutico , Ácidos Graxos/metabolismo , Perfilação da Expressão Gênica , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Glicólise/efeitos dos fármacos , Guanidinas/farmacologia , Guanidinas/uso terapêutico , Humanos , Lactamas Macrocíclicas/farmacologia , Lactamas Macrocíclicas/uso terapêutico , Metabolômica , Camundongos , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos , Proteômica , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Parkinsonism Relat Disord ; 68: 8-16, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31621627

RESUMO

Cerebellar ataxia is a hallmark of coenzyme Q10 (CoQ10) deficiency associated with COQ8A mutations. We present four patients, one with novel COQ8A pathogenic variants all with early, prominent handwriting impairment, dystonia and only mild ataxia. To better define the phenotypic spectrum and course of COQ8A disease, we review the clinical presentation and evolution in 47 reported cases. Individuals with COQ8A mutation display great clinical variability and unpredictable responses to CoQ10 supplementation. Onset is typically during infancy or childhood with ataxic features associated with developmental delay or regression. When disease onset is later in life, first symptoms can include: incoordination, epilepsy, tremor, and deterioration of writing. The natural history is characterized by a progression to a multisystem brain disease dominated by ataxia, with disease severity inversely correlated with age at onset. Six previously reported cases share with ours, a clinical phenotype characterized by slowly progressive or static writing difficulties, focal dystonia, and speech disorder, with only minimal ataxia. The combination of writing difficulty, dystonia and ataxia is a distinctive constellation that is reminiscent of a previously described clinical entity called Dystonia Ataxia Syndrome (DYTCA) and is an important clinical indicator of COQ8A mutations, even when ataxia is mild or absent.


Assuntos
Ataxia , Progressão da Doença , Distúrbios Distônicos , Escrita Manual , Heterozigoto , Doenças Mitocondriais , Proteínas Mitocondriais/genética , Debilidade Muscular , Ubiquinona/deficiência , Adulto , Ataxia/complicações , Ataxia/epidemiologia , Ataxia/etiologia , Ataxia/genética , Ataxia/fisiopatologia , Criança , Distúrbios Distônicos/epidemiologia , Distúrbios Distônicos/etiologia , Distúrbios Distônicos/genética , Distúrbios Distônicos/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/complicações , Doenças Mitocondriais/epidemiologia , Doenças Mitocondriais/genética , Doenças Mitocondriais/fisiopatologia , Debilidade Muscular/complicações , Debilidade Muscular/epidemiologia , Debilidade Muscular/genética , Debilidade Muscular/fisiopatologia , Ubiquinona/genética , Adulto Jovem
17.
Thorax ; 74(11): 1099-1101, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31534031

RESUMO

Muscle mitochondrial dysfunction is implicated in intensive care unit-acquired weakness, but there is no serum biomarker of muscle mitochondrial function for critical illness survivors. Higher serum growth differentiation factor-15 (GDF-15) is a biomarker of inherited mitochondrial myopathy disease and is associated with mortality in several age-related diseases. Among 142 older (age ≥ 65 years) survivors of acute respiratory failure, we found that higher serum GDF-15 measured during the week prior to hospital discharge was cross-sectionally associated with weaker diaphragm, limb and hand-grip strength, and longitudinally associated with lower rates of functional recovery over 6 months, independent of age, sex, pre-existing disability, comorbidity, frailty, Acute Physiology and Chronic Health Evaluation II scores and concurrent interleukin-6 levels.


Assuntos
Diafragma/fisiopatologia , Fator 15 de Diferenciação de Crescimento/sangue , Força da Mão , Insuficiência Respiratória/sangue , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Insuficiência Respiratória/fisiopatologia , Sobreviventes
18.
EMBO Mol Med ; 11(10): e10769, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31468706

RESUMO

Liver-X-receptor (LXR) agonists are known to bear anti-tumor activity. However, their efficacy is limited and additional insights regarding the underlying mechanism are necessary. By performing transcriptome analysis coupled with global polar metabolite screening, we show that LXR agonists, LXR623 and GW3965, enhance synergistically the anti-proliferative effect of BH3 mimetics in solid tumor malignancies, which is predominantly mediated by cell death with features of apoptosis and is rescued by exogenous cholesterol. Extracellular flux analysis and carbon tracing experiments (U-13 C-glucose and U-13 C-glutamine) reveal that within 5 h, activation of LXRß results in reprogramming of tumor cell metabolism, leading to suppression of mitochondrial respiration, a phenomenon not observed in normal human astrocytes. LXR activation elicits a suppression of respiratory complexes at the protein level by reducing their stability. In turn, energy starvation drives an integrated stress response (ISR) that up-regulates pro-apoptotic Noxa in an ATF4-dependent manner. Cholesterol and nucleotides rescue from the ISR elicited by LXR agonists and from cell death induced by LXR agonists and BH3 mimetics. In conventional and patient-derived xenograft models of colon carcinoma, melanoma, and glioblastoma, the combination treatment of ABT263 and LXR agonists reduces tumor sizes significantly stronger than single treatments. Therefore, the combination treatment of LXR agonists and BH3 mimetics might be a viable efficacious treatment approach for solid malignancies.


Assuntos
Carcinoma/fisiopatologia , Respiração Celular/efeitos dos fármacos , Glioblastoma/fisiopatologia , Receptores X do Fígado/agonistas , Melanoma/fisiopatologia , Proteína bcl-X/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Benzoatos/metabolismo , Benzilaminas/metabolismo , Carcinoma/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Glioblastoma/tratamento farmacológico , Humanos , Indazóis/metabolismo , Melanoma/tratamento farmacológico , Metabolômica , Modelos Teóricos , Resultado do Tratamento
19.
NPJ Genom Med ; 4: 18, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396399

RESUMO

Primary coenzyme Q10 deficiency-7 (COQ10D7) is a rare mitochondrial disease caused by biallelic mutations in COQ4. Here we report the largest cohort of COQ10D7 to date, with 11 southern Chinese patients confirmed with biallelic COQ4 mutations. Five of them have the classical neonatal-onset encephalo-cardiomyopathy, while the others have infantile onset with more heterogeneous clinical presentations. We also identify a founder mutation COQ4 (NM_016035.5): c.370G>A, p.(Gly124Ser) for COQ10D7, suggesting a higher chance of occurrence in the southern Chinese. This study helps improve understanding of the clinical spectrum of this disorder.

20.
Brain ; 142(9): 2756-2774, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31305892

RESUMO

Multiple sclerosis is an autoimmune demyelinating disorder of the CNS, characterized by inflammatory lesions and an underlying neurodegenerative process, which is more prominent in patients with progressive disease course. It has been proposed that mitochondrial dysfunction underlies neuronal damage, the precise mechanism by which this occurs remains uncertain. To investigate potential mechanisms of neurodegeneration, we conducted a functional screening of mitochondria in neurons exposed to the CSF of multiple sclerosis patients with a relapsing remitting (n = 15) or a progressive (secondary, n = 15 or primary, n = 14) disease course. Live-imaging of CSF-treated neurons, using a fluorescent mitochondrial tracer, identified mitochondrial elongation as a unique effect induced by the CSF from progressive patients. These morphological changes were associated with decreased activity of mitochondrial complexes I, III and IV and correlated with axonal damage. The effect of CSF treatment on the morphology of mitochondria was characterized by phosphorylation of serine 637 on the dynamin-related protein DRP1, a post-translational modification responsible for unopposed mitochondrial fusion in response to low glucose conditions. The effect of neuronal treatment with CSF from progressive patients was heat stable, thereby prompting us to conduct an unbiased exploratory lipidomic study that identified specific ceramide species as differentially abundant in the CSF of progressive patients compared to relapsing remitting multiple sclerosis. Treatment of neurons with medium supplemented with ceramides, induced a time-dependent increase of the transcripts levels of specific glucose and lactate transporters, which functionally resulted in progressively increased glucose uptake from the medium. Thus ceramide levels in the CSF of patients with progressive multiple sclerosis not only impaired mitochondrial respiration but also decreased the bioavailability of glucose by increasing its uptake. Importantly the neurotoxic effect of CSF treatment could be rescued by exogenous supplementation with glucose or lactate, presumably to compensate the inefficient fuel utilization. Together these data suggest a condition of 'virtual hypoglycosis' induced by the CSF of progressive patients in cultured neurons and suggest a critical temporal window of intervention for the rescue of the metabolic impairment of neuronal bioenergetics underlying neurodegeneration in multiple sclerosis patients.


Assuntos
Líquido Cefalorraquidiano/química , Metabolismo Energético/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Esclerose Múltipla Crônica Progressiva/líquido cefalorraquidiano , Esclerose Múltipla Recidivante-Remitente/líquido cefalorraquidiano , Neurônios/efeitos dos fármacos , Animais , Ceramidas/líquido cefalorraquidiano , Ceramidas/isolamento & purificação , Ceramidas/toxicidade , Dinaminas/química , Glucose/metabolismo , Glucose/farmacologia , Temperatura Alta , Microscopia Intravital , Lactatos/metabolismo , Lactatos/farmacologia , Lipidômica , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Esclerose Múltipla Crônica Progressiva/patologia , Esclerose Múltipla Recidivante-Remitente/patologia , Degeneração Neural , Fosforilação , Processamento de Proteína Pós-Traducional , Ratos
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