A acidúria combinada malônica e metilmalônica (CMAMMA), também chamada de acidemia malônica e metilmalônica combinada, é uma doença metabólica hereditária caracterizada por níveis elevados de ácido malônico e ácido metilmalônico. No entanto, os níveis de ácido metilmalónico excedem os de ácido malónico. A CMAMMA não é apenas uma acidúria orgânica, mas também um defeito da síntese mitocondrial de ácidos gordos (mtFASII). Alguns pesquisadores colocaram a hipótese de que o CMAMMA pode ser uma das formas mais comuns de acidemia metilmalônica e possivelmente um dos erros congénitos mais comuns do metabolismo. Devido ao facto de ser diagnosticado com pouca frequência, na maioria das vezes não é detectado.
Introdução
O que você precisa saber de cara
Doença rara que afeta o transporte de substratos para as mitocôndrias, causando hepatoesplenomegalia, distrofia corneana, déficits de crescimento e problemas cardíacos/respiratórios. Associada a mutações em genes como SLC25A3 e TKFC.
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Sinais e sintomas
O que aparece no corpo e com que frequência cada sintoma acontece
Partes do corpo afetadas
+ 39 sintomas em outras categorias
Características mais comuns
Os sintomas variam de pessoa para pessoa. Abaixo estão as 107 características clínicas mais associadas, ordenadas por frequência.
Linha do tempo da pesquisa
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Genética e causas
O que está alterado no DNA e como passa nas famílias
Genes associados
7 genes identificados com associação a esta condição.
Inorganic ion transporter that transports phosphate or copper ions across the mitochondrial inner membrane into the matrix compartment (By similarity) (PubMed:17273968, PubMed:29237729). Mediates proton-coupled symport of phosphate ions necessary for mitochondrial oxidative phosphorylation of ADP to ATP (By similarity) (PubMed:17273968). Transports copper ions probably in the form of anionic copper(I) complexes to maintain mitochondrial matrix copper pool and to supply copper for cytochrome C ox
Mitochondrion inner membrane
Mitochondrial phosphate carrier deficiency
An autosomal recessive disorder of oxidative phosphorylation. Patients have lactic acidosis, hypertrophic cardiomyopathy and muscular hypotonia and die within the first year of life.
Catalyzes both the phosphorylation of dihydroxyacetone and of glyceraldehyde, and the splitting of ribonucleoside diphosphate-X compounds among which FAD is the best substrate. Represses IFIH1-mediated cellular antiviral response (PubMed:17600090)
Triokinase and FMN cyclase deficiency syndrome
An autosomal recessive disease characterized by cataracts and developmental delay that may be associated with cerebellar hypoplasia. Additional features may include liver dysfunction, microcytic anemia, and fatal cardiomyopathy with lactic acidosis following a febrile illness.
ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell (PubMed:21586654, PubMed:27693233, PubMed:23173940, PubMed:30046662). Cycles between the cytoplasmic-open state (c-state) and the matrix-open state (m-state): operates by the alternating access mechanism with a single substrate-binding site intermittently exposed to either the cytosolic (c-state) or matrix (m-state) side of the inner mitochondrial membrane (By si
Mitochondrion inner membraneMembrane
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 2
A disorder characterized by progressive weakness of ocular muscles and levator muscle of the upper eyelid. In a minority of cases, it is associated with skeletal myopathy, which predominantly involves axial or proximal muscles and which causes abnormal fatigability and even permanent muscle weakness. Ragged-red fibers and atrophy are found on muscle biopsy. A large proportion of chronic ophthalmoplegias are associated with other symptoms, leading to a multisystemic pattern of this disease. Additional symptoms are variable, and may include cataracts, hearing loss, sensory axonal neuropathy, ataxia, depression, hypogonadism, and parkinsonism.
Lipid kinase that can phosphorylate both monoacylglycerol and diacylglycerol to form lysophosphatidic acid (LPA) and phosphatidic acid (PA), respectively (PubMed:15939762). Does not phosphorylate sphingosine (PubMed:15939762). Phosphorylates ceramide (By similarity). Phosphorylates 1,2-dioleoylglycerol more rapidly than 2,3-dioleoylglycerol (By similarity). Independently of its lipid kinase activity, acts as a component of the TIM22 complex (PubMed:28712724, PubMed:28712726). The TIM22 complex m
Mitochondrion inner membraneMitochondrion intermembrane space
Mitochondrial DNA depletion syndrome 10
An autosomal recessive mitochondrial disorder characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance, and lactic acidosis. Mental development is normal, but affected individuals may die early from cardiomyopathy.
Monothiol glutaredoxin involved in mitochondrial iron-sulfur (Fe/S) cluster transfer (PubMed:20364084, PubMed:23615440). Receives 2Fe/2S clusters from scaffold protein ISCU and mediates their transfer to apoproteins, to the 4Fe/FS cluster biosynthesis machinery, or export from mitochondrion (PubMed:20364084, PubMed:23615440, PubMed:24334290). Required for normal regulation of hemoglobin synthesis by the iron-sulfur protein ACO1 (PubMed:20364084)
Mitochondrion matrix
Anemia, sideroblastic, 3, pyridoxine-refractory
A form of sideroblastic anemia, a bone marrow disorder defined by the presence of pathologic iron deposits in erythroblast mitochondria. Sideroblastic anemia is characterized by anemia of varying severity, hypochromic peripheral erythrocytes, systemic iron overload secondary to chronic ineffective erythropoiesis, and the presence of bone marrow ringed sideroblasts. Sideroblasts are characterized by iron-loaded mitochondria clustered around the nucleus. SIDBA3 is refractory to treatment with vitamin B6, while iron chelation therapy may result in clinical improvement. SIDBA3 inheritance is autosomal recessive.
Mitochondrial S-adenosyl-L-methionine/S-adenosyl-L-homocysteine antiporter. Mediates the exchange of cytosolic S-adenosyl-L-methionine, the predominant methyl-group donor for macromolecule methylation processes, for mitochondrial S-adenosylhomocysteine(SAH), a by-product of methylation reactions
Mitochondrion inner membrane
Combined oxidative phosphorylation deficiency 28
An autosomal recessive mitochondrial disorder characterized by decreased activities of respiratory chain enzymes, and variable clinical manifestations. Clinical features include episodic metabolic decompensation beginning in infancy, mild muscle weakness, cardiorespiratory insufficiency, developmental delay, or even death.
Mitochondrial electrogenic aspartate/glutamate antiporter that favors efflux of aspartate and entry of glutamate and proton within the mitochondria as part of the malate-aspartate shuttle (PubMed:11566871, PubMed:19641205, PubMed:24515575, PubMed:38945283). Also mediates the uptake of L-cysteinesulfinate (3-sulfino-L-alanine) by mitochondria in exchange of L-glutamate and proton (PubMed:11566871). Can also exchange L-cysteinesulfinate with aspartate in their anionic form without any proton trans
Mitochondrion inner membrane
Developmental and epileptic encephalopathy 39 with leukodystrophy
A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE39 is characterized by global hypomyelination of the central nervous system, with the gray matter appearing relatively unaffected. Inheritance is autosomal recessive.
Variantes genéticas (ClinVar)
195 variantes patogênicas registradas no ClinVar.
Vias biológicas (Reactome)
18 vias biológicas associadas aos genes desta condição.
Diagnóstico
Os sinais que médicos procuram e os exames que confirmam
Tratamento e manejo
Remédios, cuidados de apoio e o que precisa acompanhar
Onde tratar no SUS
Hospitais de referência no Brasil e o protocolo oficial do SUS (PCDT)
🇧🇷 Atendimento SUS — Doença do transportador de substrato mitocondrial
Selecione um estado ou use sua localização para ver resultados.
Dados de DATASUS/CNES, SBGM, ABNeuro e Ministério da Saúde. Sempre confirme a disponibilidade diretamente com o estabelecimento.
Pesquisa ativa
Ensaios clínicos abertos e novidades científicas recentes
Pesquisa e ensaios clínicos
Nenhum ensaio clínico registrado para esta condição.
Publicações mais relevantes
Structural transport and inhibition mechanism of the mitochondrial pyruvate carrier.
The mitochondrial pyruvate carrier (MPC), of the SLC54 family of solute carriers, has a critical role in eukaryotic energy metabolism by transporting pyruvate, the end-product of glycolysis, into the mitochondrial matrix. Recently, structures of the human MPC1/MPC2 and MPC1L/MPC2 heterodimers in the outward-open, occluded, and inward-open states have been determined by cryo-electron microscopy (cryo-EM) and by AlphaFold modeling. In this review we discuss the membrane orientation, substrate binding site properties, and structural features of the alternating access mechanism of the carrier, as well as the binding poses of three chemically distinct inhibitor classes, which exploit the same binding site in the outward-open state. These structural studies will support drug development efforts for the treatment of diabetes mellitus, neurodegeneration, metabolic dysfunction-associated steatotic liver disease (MASLD), and some types of cancers.
Rationally engineered cyclodextrins: smart shuttles for neurological drug targeting and BBB modulation.
The pathophysiology of neurodegenerative disorders during therapeutic intervention presents significant challenges, largely stemming from the selective permeability of blood-brain barrier (BBB), limited drug solubility, and idiosyncratic pharmacodynamic interactions. This inherent impermeability of the BBB to conventional xenobiotics/drugs significantly impedes their neurotherapeutic efficacy by restricting access to critical neural substrates. Cyclodextrins (CDs), a class of cyclic oligosaccharides with α-(1,4)-linked glucopyranose units, have emerged as innovative drug delivery vectors capable of addressing these limitations. Their unique toroidal supramolecular architecture, distinguished by a hydrophobic central cavity and a hydrophilic external surface, facilitates the formation of stable inclusion complexes with lipophilic pharmacophores, thereby enhancing their aqueous solubility and improving pharmacokinetic parameters. It also exhibits potent cholesterol-sequestering capabilities, exerting neuroprotective effects through modulation of membrane lipid homeostasis, upregulation of autophagic flux, and optimization of mitochondrial bioenergetics in neural tissue. The present review succinctly elucidates the nuanced mechanistic intricacies of contemporary CD-based drug delivery systems in traversing the BBB, augmenting targeted drug biodistribution, and modulating protein-lipid interactions at the molecular level, offering a novel therapeutic paradigm for an array of neurodegenerative pathologies. Emphasis is placed on elucidating the mechanism of drug encapsulation and release from CD-drug conjugates, their interactions with membrane lipids and efflux transporters, and their potential to modulate neuroinflammatory cascades and protein aggregation process.
Nanoscale conformational dynamics of human propionyl-CoA carboxylase.
Propionyl-CoA carboxylase (PCC) is a biotin-dependent mitochondrial enzyme responsible for propionyl-CoA catabolism. Deficiencies in human PCC (hPCC) cause propionic acidemia, a severe metabolic disorder driven by toxic metabolite accumulation. Despite its therapeutic relevance, the structural basis of hPCC's catalytic function remains unresolved. Here, we present high-resolution cryo-EM structures of hPCC in four distinct states, unliganded, ADP-, AMPPNP-, and ATP-bound/substrate-bound, capturing the full trajectory of the biotin carboxyl carrier protein (BCCP) domain as it translocates between active sites. Our results reinforce the crucial role of nucleotide-gated B-lid subdomain in synchronizing catalysis through coupling with BCCP movement. Structural and biochemical analysis of 10 disease-associated variants reveals how mutations disrupt key domain interfaces and dynamic motions required for activity. These new insights define the mechanistic principles governing hPCC functions, establish a structural framework for understanding PCC-related disorders, and lay the groundwork for future efforts to engineer functional replacements or modulators for metabolic therapy.
A repurposed AMP binding domain reveals mitochondrial protein AMPylation as a regulator of cellular metabolism.
Protein AMPylation, the covalent addition of adenosine monophosphate (AMP) to protein substrates, has been known as a post translational modification for over 50 years. Research in this field is largely underdeveloped due to the lack of tools that enable the systematic identification of AMPylated substrates. Here, we address this gap by developing an enrichment technique to isolate and study AMPylated proteins using a nucleotide-binding protein, hinT. Cryo-EM reconstruction of an AMPylated protein bound to hinT provides a structural basis for AMP selectivity. Using structure guided mutagenesis, we optimize enrichment to identify novel substrates of the evolutionarily conserved AMPylase, Selenoprotein O. We show that mammalian Selenoprotein O regulates metabolic flux through AMPylation of key mitochondrial proteins including glutamate dehydrogenase and pyruvate dehydrogenase. Our findings highlight the broader significance of AMPylation, an emerging post translational modification with critical roles in signal transduction and disease pathology. Furthermore, we establish a powerful enrichment platform for the discovery of novel AMPylated proteins to study the mechanisms and significance of protein AMPylation in cellular function.
SIRT3 deficiency aggravates mitochondrial metabolic disorder and podocyte injury in DKD via MPC2 acetylation.
Diabetic kidney disease (DKD) is a chronic disease characterized by high prevalence and mortality rates. Podocyte injury and mitochondrial metabolic disorder are crucial in its progression. Sirtuin3 (SIRT3), a mitochondrial NAD+-dependent deacetylase, exerts renoprotective effects in various kidney pathologies by modulating the acetylation status and activity of energy metabolism related substrates. However, its specific roles in podocytes homeostasis during DKD progression remain unclear. We previously reported the role and acetylation level of mitochondrial pyruvate carrier 2 (MPC2) in DKD, but the regulatory mechanism between SIRT3 and MPC2 has not been elucidated. This study aims to investigate the effect of SIRT3 on mitochondrial reprogramming in podocytes and explore the association between SIRT3 and MPC2 during DKD progression. SIRT3 expression was downregulated in hyperglycemia-induced podocytes in vivo and in vitro. SIRT3 deficiency aggravated podocyte apoptosis and mitochondrial homeostasis dysregulation, as evidenced by increased ROS production, decreased mitochondrial membrane potential and diminished ATP level. However, the overexpression of SIRT3 alleviated these alterations. In addition, we identified a binding interaction between SIRT3 and MPC2. SIRT3 deacetylated MPC2 at lysine K19/K27, mechanistically implicated in the podocyte injury in the process of DKD. This study validated that hyperglycemia-induced SIRT3-mediated MPC2 acetylation contributes to mitochondrial dysfunction and cellular apoptosis.
Publicações recentes
Hemocyte RNA-Seq analysis of Indian malarial vectors Anopheles stephensi and Anopheles culicifacies: From similarities to differences.
Serine hydroxymethyltransferase localised in the endoplasmic reticulum plays a role in scavenging H(2)O(2) to enhance rice chilling tolerance.
Alkanols inhibit respiration of intact mitochondria and display cutoff similar to that measured in vivo.
📚 EuropePMCmostrando 92
Rationally engineered cyclodextrins: smart shuttles for neurological drug targeting and BBB modulation.
Bioorganic chemistryStructural transport and inhibition mechanism of the mitochondrial pyruvate carrier.
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Scientific reportsNanoscale conformational dynamics of human propionyl-CoA carboxylase.
Structure (London, England : 1993)A repurposed AMP binding domain reveals mitochondrial protein AMPylation as a regulator of cellular metabolism.
Nature communicationsSIRT3 deficiency aggravates mitochondrial metabolic disorder and podocyte injury in DKD via MPC2 acetylation.
Cellular signallingUpdate of the sideroflexin (SLC56) gene family.
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The Journal of biological chemistryCurrent Understanding of Pathogenic Mechanisms and Disease Models of Citrin Deficiency.
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Science (New York, N.Y.)The Role of Solute Carrier Family Transporters in Hepatic Steatosis and Hepatic Fibrosis.
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Current medicinal chemistryA novel remitting leukodystrophy associated with a variant in FBP2.
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The Biochemical journalAssociações
Organizações que acompanham esta doença — pra ter apoio e orientação
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Referências e fontes
Bases de dados externas citadas neste artigo
Publicações científicas
Artigos indexados no PubMed ligados a esta doença no grafo RarasNet — título, periódico e PMID direto da fonte, sem intermediação de IA.
- Structural transport and inhibition mechanism of the mitochondrial pyruvate carrier.
- Rationally engineered cyclodextrins: smart shuttles for neurological drug targeting and BBB modulation.
- Nanoscale conformational dynamics of human propionyl-CoA carboxylase.
- A repurposed AMP binding domain reveals mitochondrial protein AMPylation as a regulator of cellular metabolism.
- SIRT3 deficiency aggravates mitochondrial metabolic disorder and podocyte injury in DKD via MPC2 acetylation.
- Hemocyte RNA-Seq analysis of Indian malarial vectors Anopheles stephensi and Anopheles culicifacies: From similarities to differences.
- Serine hydroxymethyltransferase localised in the endoplasmic reticulum plays a role in scavenging H(2)O(2) to enhance rice chilling tolerance.
- Alkanols inhibit respiration of intact mitochondria and display cutoff similar to that measured in vivo.
Bases de dados e fontes oficiais
Identificadores e referências canônicas usadas para montar este verbete.
- ORPHA:254830(Orphanet)
- MONDO:0016801(MONDO)
- GARD:20762(GARD (NIH))
- Variantes catalogadas(ClinVar)
- Busca completa no PubMed(PubMed)
- Q55786461(Wikidata)
Dados compilados pelo RarasNet a partir de fontes abertas (Orphanet, OMIM, MONDO, PubMed/EuropePMC, ClinicalTrials.gov, DATASUS, PCDT/MS). Este conteúdo é informativo e não substitui avaliação médica.
Conteúdo mantido por Agente Raras · Médicos e pesquisadores podem colaborar
