SLC25A10 biallelic mutations in intractable epileptic encephalopathy with complex I deficiency

Punzi, Giuseppe; Porcelli, Vito; Ruggiu, Matteo; Hossain, Faruk; Menga, Alessio; Scarcia, Pasquale; Castegna, Alessandra; Gorgoglione, Ruggiero; Pierri, Ciro Leonardo; Laera, Luna; Lasorsa, Francesco M.; Paradies, Eleonora; Pisano, Isabella; Marobbio, C; Lamantea, Eleonora; Ghezzi, Daniele; Tiranti, Valeria; Giannattasio, Sergio; Guerrini, Renzo; Palmieri, Luigi; Palmieri, Ferdinando; Grassi, Anna

doi:10.1093/hmg/ddx419

Cited by 38 publications

(41 citation statements)

References 26 publications

(34 reference statements)

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“…47 Moreover, it is well known that homozygous or compound heterozygous mutations in TCA-cycle-related genes (e.g., SDH genes, FH, MDH2, ACO2 [MIM: 100850], IDH3A [MIM: 601149], or SLC25A10), lead to encephalopathy and neurodegeneration. [48][49][50][51][52] Thus, if one takes into account the evidences linking intermediary metabolism, tumorigenesis, and neurodegeneration, it is not surprising to find that mutations in DLST lead to cancer.…”

Section: Discussionmentioning

confidence: 99%

Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas

Remacha

Pirman

Mahoney

et al. 2019

The American Journal of Human Genetics

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Pheochromocytomas and paragangliomas (PPGLs) provide some of the clearest genetic evidence for the critical role of metabolism in the tumorigenesis process. Approximately 40% of PPGLs are caused by driver germline mutations in 16 known susceptibility genes, and approximately half of these genes encode members of the tricarboxylic acid (TCA) cycle. Taking as a starting point the involvement of the TCA cycle in PPGL development, we aimed to identify unreported mutations that occurred in genes involved in this key metabolic pathway and that could explain the phenotypes of additional individuals who lack mutations in known susceptibility genes. To accomplish this, we applied a targeted sequencing of 37 TCA-cycle-related genes to DNA from 104 PPGL-affected individuals with no mutations in the major known predisposing genes. We also performed omics-based analyses, TCA-related metabolite determination, and 13 C 5 -glutamate labeling assays. We identified five germline variants affecting DLST in eight unrelated individuals ($7%); all except one were diagnosed with multiple PPGLs. A recurrent variant, c.1121G>A (p.Gly374Glu), found in four of the eight individuals triggered accumulation of 2-hydroxyglutarate, both in tumors and in a heterologous cell-based assay designed to functionally evaluate DLST variants. p.Gly374Glu-DLST tumors exhibited loss of heterozygosity, and their methylation and expression profiles are similar to those of EPAS1-mutated PPGLs; this similarity suggests a link between DLST disruption and pseudohypoxia. Moreover, we found positive DLST immunostaining exclusively in tumors carrying TCA-cycle or EPAS1 mutations. In summary, this study reveals DLST as a PPGL-susceptibility gene and further strengthens the relevance of the TCA cycle in PPGL development.

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Section: Discussionmentioning

confidence: 99%

Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas

Remacha

Pirman

Mahoney

et al. 2019

The American Journal of Human Genetics

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“…Thus, it appears that other mitochondrial enzymes may contribute to the buffering of altered NAD + /NADH ratios by oxidizing alternatively cytosolic NADH or mitochondrial matrix NADH, and here, we might speculate that AIF, being anchored to the mitochondrial inner membrane, protruding into the intermembrane space, may participate in the regulation of the NAD + /NADH or FAD/FADH2 (maybe UQ/UQH2) ratio. AIF participation in the regulation of redox signaling between mitochondria and other cell compartments may be crucial above all in those tissues in which the G3P shuttle [69], nicotinamide nucleotide transhydrogenase (NNT) [70], NADH-b5 oxidoreductase [71,72], or malate/aspartate shuttle [15,73,74] do not work properly or when the cited proteins, mitochondrial oxidative phosphorylation complex subunits, or matrix proteins are mutated or downregulated [75,76]. If AIF behaves as a NADH dehydrogenase, able to oxidize cytosolic NADH, it may also participate in reprogramming metabolic pathways, providing new clues towards the full comprehension of the puzzling Warburg effect condition [77].…”

Section: New Clues In Support Of Aif Participation In Mitochondrial Rmentioning

confidence: 99%

FAD/NADH Dependent Oxidoreductases: From Different Amino Acid Sequences to Similar Protein Shapes for Playing an Ancient Function

Trisolini

Gambacorta

Gorgoglione

et al. 2019

JCM

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Flavoprotein oxidoreductases are members of a large protein family of specialized dehydrogenases, which include type II NADH dehydrogenase, pyridine nucleotide-disulphide oxidoreductases, ferredoxin-NAD+ reductases, NADH oxidases, and NADH peroxidases, playing a crucial role in the metabolism of several prokaryotes and eukaryotes. Although several studies have been performed on single members or protein subgroups of flavoprotein oxidoreductases, a comprehensive analysis on structure–function relationships among the different members and subgroups of this great dehydrogenase family is still missing. Here, we present a structural comparative analysis showing that the investigated flavoprotein oxidoreductases have a highly similar overall structure, although the investigated dehydrogenases are quite different in functional annotations and global amino acid composition. The different functional annotation is ascribed to their participation in species-specific metabolic pathways based on the same biochemical reaction, i.e., the oxidation of specific cofactors, like NADH and FADH2. Notably, the performed comparative analysis sheds light on conserved sequence features that reflect very similar oxidation mechanisms, conserved among flavoprotein oxidoreductases belonging to phylogenetically distant species, as the bacterial type II NADH dehydrogenases and the mammalian apoptosis-inducing factor protein, until now retained as unique protein entities in Bacteria/Fungi or Animals, respectively. Furthermore, the presented computational analyses will allow consideration of FAD/NADH oxidoreductases as a possible target of new small molecules to be used as modulators of mitochondrial respiration for patients affected by rare diseases or cancer showing mitochondrial dysfunction, or antibiotics for treating bacterial/fungal/protista infections.

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“…Mammalian DIC was shown to transport dicarboxylates such as malate and succinate as well as inorganic anions such as phosphate, sulfate, and thiosulfate by a strict electroneutral counter-exchange ( Figure 3) [64,67,68,[81][82][83][84]. As shown by transport experiments with isolated mitochondrial membranes from patient fibroblasts fused with liposomes, the malate/phosphate exchange was dramatically reduced [80]. It was also observed that the ratios of NADPH/NADP + and GSH/GSSG were decreased.…”

Section: Slc25a10 (Dicarboxylate Carrier Dic) Deficiencymentioning

confidence: 96%

“…One patient with a severe neurodegenerative disorder, characterized by epileptic encephalopathy, complex I deficiency, and mitochondrial DNA depletion in skeletal muscle was shown to possess mutations in the gene SLC25A10 [80]. The heterozygous mutations of the patient (a silent and an intron mutation in one allele and a frame shift mutation in the other, Table S1) resulted in reduced RNA quantity and malfunctional splicing, leading to the absence of the dicarboxylate carrier DIC (encoded by SLC25A10).…”

Section: Slc25a10 (Dicarboxylate Carrier Dic) Deficiencymentioning

confidence: 99%

Diseases Caused by Mutations in Mitochondrial Carrier Genes SLC25: A Review

2020

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In the 1980s, after the mitochondrial DNA (mtDNA) had been sequenced, several diseases resulting from mtDNA mutations emerged. Later, numerous disorders caused by mutations in the nuclear genes encoding mitochondrial proteins were found. A group of these diseases are due to defects of mitochondrial carriers, a family of proteins named solute carrier family 25 (SLC25), that transport a variety of solutes such as the reagents of ATP synthase (ATP, ADP, and phosphate), tricarboxylic acid cycle intermediates, cofactors, amino acids, and carnitine esters of fatty acids. The disease-causing mutations disclosed in mitochondrial carriers range from point mutations, which are often localized in the substrate translocation pore of the carrier, to large deletions and insertions. The biochemical consequences of deficient transport are the compartmentalized accumulation of the substrates and dysfunctional mitochondrial and cellular metabolism, which frequently develop into various forms of myopathy, encephalopathy, or neuropathy. Examples of diseases, due to mitochondrial carrier mutations are: combined D-2- and L-2-hydroxyglutaric aciduria, carnitine-acylcarnitine carrier deficiency, hyperornithinemia-hyperammonemia-homocitrillinuria (HHH) syndrome, early infantile epileptic encephalopathy type 3, Amish microcephaly, aspartate/glutamate isoform 1 deficiency, congenital sideroblastic anemia, Fontaine progeroid syndrome, and citrullinemia type II. Here, we review all the mitochondrial carrier-related diseases known until now, focusing on the connections between the molecular basis, altered metabolism, and phenotypes of these inherited disorders.

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SLC25A10 biallelic mutations in intractable epileptic encephalopathy with complex I deficiency

Cited by 38 publications

References 26 publications

Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas

Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas

FAD/NADH Dependent Oxidoreductases: From Different Amino Acid Sequences to Similar Protein Shapes for Playing an Ancient Function

Diseases Caused by Mutations in Mitochondrial Carrier Genes SLC25: A Review

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