Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE41044 | GEO | 2013/05/01
SECONDARY ACCESSION(S): PRJNA175609
REPOSITORIES: GEO
Similar Datasets
Project description:Isolated methylmalonic acidemia (MMA) is a pleiotropic enzymatic defect of branched-chain amino acid oxidation most commonly caused by deficiency of methylmalonyl-CoA mutase (MUT). End stage renal disease (ESRD) is emerging as an inevitable disease-related complication, recalcitrant to conventional therapies and liver transplantation. To establish a viable model of MMA-associated renal disease, methylmalonyl-CoA mutase (Mut) was expressed in the liver of Mut -/- mice as a stable transgene under the control of an albumin (INS-Alb-Mut) promoter. Mut -/- ;TgINS-Alb-Mut mice were rescued from the neonatal lethality displayed by Mut -/- mice and manifested a decreased glomerular filtration rate (GFR), chronic tubulointerstital nephritis (CTIN) and prominent ultrastructural changes in the proximal tubular mitochondria, replicating precisely the renal manifestations seen in a large MMA patient cohort. To explore the pathophysiological changes that underlie the renal disease of MMA, we compared gene expression profiles of whole kidney mRNA samples between 4 female Mut +/+, Mut +/- and Mut -/- ;TgINS-Alb-Mut mice after they ingested a HP diet for 2 months. Females were used because more survived the dietary challenge, whereas the histology, ultrastructure and GFR effects were identical between sexes
2013-05-01 | E-GEOD-41044 | biostudies-arrayexpress
Project description:Methylmalonic acidemia (MMA), an organic acidemia characterized by metabolic instability and multiorgan complications, is most frequently caused by mutations in methylmalonyl-CoA mutase (MUT). To define the metabolic adaptations in MMA, in the chronic and acute settings, we studied a mouse model generated by transgenic expression of Mut in the muscle. Mut-/-;TgINS-MCK-Mut mice accurately replicate the hepato-renal mitochondriopathy and growth failure seen in severely affected patients, and were used to characterize the response to fasting. The hepatic transcriptome in MMA mice was characterized by the chronic activation of stress-related pathways and responded abberrantly to fasting when compared to controls.
2019-08-01 | GSE118862 | GEO
Project description:Methylmalonic acidemia (MMA) is one of the most common inherited metabolic disorders, due to deficiency of the mitochondrial methylmalonyl ̶ coenzyme A mutase (MUT). How MUT deficiency triggers mitochondrial alterations and cell damage remains unknown, preventing the development of disease-modifying therapies. To assess the effect of MUT deficiency on gene expression we investigated the transcriptome of in kidney cells derived from healthy controls or patients with MMA who harbor inactivating mutations in MUT. Microarray data indicate that MUT deficiency induces a profound and global change in gene expression that may be in part responsible of cellular alterations observed in patient cells.
2019-10-01 | GSE120683 | GEO
Project description:Methylmalonic acidemias (MMA) consist in a group of autosomal recessive inherited metabolic disorders whose pathogenesis involves the catabolism of propionyl-CoA. The propionyl-CoA produced from the degradation of cholesterol, branched-chain amino acids (valine, isoleucine, methionine, threonine) and the -oxidation of odd-chain fatty acids is converted into methylmalonyl-CoA, which is further converted in succinyl-CoA, required for energy production in the Krebs cycle. In mitochondria of MMA patients, the conversion of methylmalonyl-CoA into succinyl-CoA, catalysed by the vitamin B12-dependent methylmalonyl-CoA mutase (MUT) enzyme, is altered. This can be due to: 1) defective activity of MUT apoenzyme or 2) a defect in the synthesis or transport of adenosylcobalamin (MUT cofactor). In the first case it is referred to as isolated MMA (mut0 or mut- phenotypes if the deficiency is total or partial, respectively), while in the second case as cbl-related MMA (there is a specific disorder according to which gene is mutated) []. The blockage of this enzymatic reaction leads to increase in the levels of methylmalonic acid, hallmark of this group of diseases []. Independently from the pathogenesis, along with methylmalonic acid, other MMA-associated metabolites like acylcarnitines, amino acids and organic acids result altered in MMA [REF]. These metabolites are easily detectable and quantifiable by metabolomics approaches, such as liquid chromatography - tandem mass spectrometry (LC-MS/MS) or gas chromatography - mass spectrometry (GC-MS), in dried blood spots or urine or plasma to make diagnosis. Because of the early onset of MMA in patients, MMA is included in the panel of diseases for the expanded newborn screening in several countries, including Italy [ref]. Our work aims at understanding the mechanisms of cellular damage in MMA disease. The majority of MMA complications arise from brain damage, on which depend neurological alterations and movement disorders. In the brain, the astrocytes are damaged by hyperammonemia, causing edema and hypoperfusion. (REF lavoro) Renal function is commonly compromised in MMA patients, even the pathogenesis of kidney injury is not clear. Renal insufficiency and chronic kidney disease are partially resolved after kidney transplantation. Hyperammonemia and metabolic acidosis are considered as key mechanisms acting in the proximal tubule to lead to renal damage. In fact, general organ metabolic alterations are thought to be caused by the breakdown of branched‐chain amino acids that lead to the accumulation of circulating toxic acidic metabolites. Thus, metabolic acidosis is induced with diminishing of bicarbonate levels. Lactic acidosis and hyperammonemia result as the main metabolic alterations of MMA. (REF lavoro) Results of a previous work on a MUT-knockdown neuroblastoma cell line [Costanzo, 2018] were coherent with the disease, but did not completely elucidate such mechanisms, possibly due to limitation of the cellular model. We presumed that the transient silencing of MUT gene was not sufficient to input long-term decompensation due to absence of this protein. For this reason, we have developed a new cellular model for isolated MMA by stably knocking out MUT gene in HEK293 cell line using CRISPR/CAS9 genome editing technology. We also performed a global proteomic analysis to describe protein changes strictly connected to MUT absence and related altered pathways. Altogether, the results obtained shed new light on the molecular mechanisms of cellular damage, including alterations of cell architecture in combination with the acquisition of a higher sensitivity to stress.
2020-09-07 | PXD017977 | Pride
Project description:2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental contaminant which induces diverse biological and toxic effects, including the reprograming of intermediate metabolism, mediated by the aryl hydrocarbon receptor (AHR). Targeted LC-MS analysis of hepatic extracts from mice gavaged with TCDD every 4 days for 28 days detected an increase in S-(2-carboxyethyl)-L-cysteine, a conjugate produced following the spontaneous reaction between the sulfhydryl group of cysteine and highly reactive acrylyl-CoA, an intermediate in the cobalamin (Cbl)-independent β–oxidation-like metabolism of propionyl-CoA. In addition to repressing genes in both the canonical Cbl-dependent carboxylase and the alternate Cbl-independent β–oxidation-like pathways at 30 µg/kg TCDD, methylmalonyl-CoA mutase (MUT) activity was inhibited at lower doses. Moreover, TCDD decreased serum Cbl levels and hepatic cobalt levels while eliciting negligible effects on gene expression associated with Cbl absorption, transport, trafficking, or the derivatization to 5’-deoxy-adenosylcobalamin (AdoCbl), the required MUT cofactor. In addition to inducing Acod1 that encodes for aconitate decarboxylase 1, the enzyme responsible for the decarboxylation cis-aconitate to itaconate, TCDD also dose-dependently increased itaconate levels in hepatic extracts. MUT inhibition is consistent with itaconate activation to itaconyl-CoA, a MUT suicide inactivator that adducts AdoCbl, that in turn, inhibits MUT activity and reduces Cbl levels. Collectively, these results suggest the decrease in MUT activity is due to Cbl depletion following TCDD treatment that redirected propionyl-CoA metabolism to the alternate Cbl-independent β–oxidation-like pathway. The resulting hepatic accumulation of acrylyl-CoA likely contributes to TCDD-elicited hepatotoxicity and the multi-hit progression of steatosis to steatohepatitis with fibrosis.
2022-08-05 | GSE203302 | GEO
Project description:Hormesis underlies the adaptive response in methylmalonic acidemia (MMA)
| PRJNA487064 | ENA
Project description:Branched-chain amino acids (BCAA) have emerged as predictors of type 2 diabetes (T2D). However, their potential role in the pathogenesis of insulin resistance and T2D remains unclear. By integrating data from skeletal muscle gene expression and metabolomic analyses, we demonstrate evidence for perturbation in BCAA metabolism and fatty acid oxidation in skeletal muscle from insulin-resistant humans. Experimental modulation of BCAA flux in cultured cells alters fatty acid oxidation in parallel. Furthermore, heterozygosity for the BCAA metabolic enzyme methylmalonyl-CoA mutase (MUT) alters muscle lipid metabolism in vivo, resulting in increased muscle triacylglycerol (TAG) accumulation and increased body weight after high-fat feeding. Together, our results demonstrate that impaired muscle BCAA catabolism may contribute to the development of insulin resistance by reducing fatty acid oxidation and increasing TAG accumulation.
2017-02-09 | GSE66766 | GEO
Project description:Cobalamin C deficiency (cblC), the most common inborn error of intracellular cobalamin metabolism, is caused by mutations in MMACHC, a gene responsible for the processing and intracellular trafficking of vitamin B12. This recessive disorder is characterized by a failure to metabolize cobalamin into adenosyl- and methylcobalamin, which results in the biochemical perturbations of methylmalonic acidemia, hyperhomocysteinemia, and hypomethioninemia caused by impaired activity of the downstream enzymes, methylmalonyl-CoA mutase and methionine synthase. Cobalamin C deficiency can be accompanied by a wide spectrum of clinical manifestations, including progressive blindness, and in mice, manifests with very early embryonic lethality. Because zebrafish harbor a full complement of cobalamin metabolic enzymes, we used genome editing to study loss of mmachc function. mmachc homozygotes survived the embryonic period but perished in early juvenile life. The mutants displayed metabolic and clinical features of cblC deficiency including methylmalonic acidemia, severe growth retardation, and lethality. Clinical and metabolic parameters improved when the mutants were raised in water supplemented with small molecules used to treat patients, including hydroxocobalamin, methylcobalamin, methionine, and betaine. Furthermore, mmachc mutants, some bred to express rod and or cone fluorescent reporters, manifested a retinopathy and thin optic nerves. Expression analysis using whole eye mRNA revealed dysregulation of genes involved in phototransduction and cholesterol metabolism. Zebrafish with mmachc deficiency recapitulate the phenotypic and biochemical features of the human disorder, including ocular pathology, and a show a response to established treatments
2019-12-01 | GSE130433 | GEO
Project description:The alteration of metabolic pathways is a critical strategy for cancer cells to attain the traits necessary for metastasis in disease progression. We found that dysregulation of propionate metabolism occurs through TGFbeta- and ERK2-driven downregulation of methylmalonyl-CoA epimerase (MCEE). MCEE downregulation occurs through a transcription factor Sp1/EGR1 switch at its promoter region, resulting in reduced flux through this anapleurotic pathway and leading to accumulation of methylmalonic acid (MMA), a byproduct of the propionate metabolism. MMA accumulation through alteration of propionate metabolism produces a pro-aggressive signature in breast and lung cancer cells and increases their metastatic potential. Altogether, we present a previously uncharacterized dysregulation of propionate metabolism as a novel contributor to cancer and a valuable potential target in the therapeutic treatment of metastatic carcinomas.
2022-01-28 | GSE161108 | GEO
Project description:From age 65 onwards, the risk of cancer incidence and associated mortality is substantially higher. Nonetheless, our understanding of the complex relationship between age and cancer is still in its infancy. For decades, the link has largely been attributed to increased exposure time to mutagens in older individuals. However, this view does not account for the well-established role of diet, exercise and small molecules that target the pace of metabolic aging. Here, we show that metabolic alterations that occur with age can render a systemic environment favorable to progression and aggressiveness of tumors. Specifically, we show that methylmalonic acid (MMA), a by-product of propionate metabolism, is significantly up-regulated in the serum of older people, and functions as a mediator of tumor progression. We traced this to the induction of SOX4 and a consequent transcriptional reprogramming that can endow cancer cells with aggressive properties. Thus, accumulation of MMA represents a novel link between aging and cancer progression, implicating MMA as a novel therapeutic target for advanced carcinomas.
2020-07-03 | GSE127001 | GEO