Methylmalonic acidemia triggers lysosomal-autophagy dysfunctions
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Q Exactive
ORGANISM(S): Homo Sapiens (human)
TISSUE(S): Kidney
DISEASE(S): Methylmalonic Aciduria Due To Methylmalonyl-coa Mutase Deficiency
SUBMITTER: 
Laxmikanth Kollipara
LAB HEAD: Prof. Dr.
PROVIDER: PXD044101 | Pride | 2024-05-23
REPOSITORIES: Pride
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| DDA_SpectralLibrary.pep.xml | Pepxml | |||
| MS_Filenames.xlsx | Xlsx | |||
| checksum.txt | Txt | |||
| qExHF01_08650.raw | Raw | |||
| qExHF01_08651.raw | Raw |
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Publications
Methylmalonic acidemia triggers lysosomal-autophagy dysfunctions.
Costanzo Michele M Cevenini Armando A Kollipara Laxmikanth L Caterino Marianna M Bianco Sabrina S Pirozzi Francesca F Scerra Gianluca G D'Agostino Massimo M Pavone Luigi Michele LM Sickmann Albert A Ruoppolo Margherita M
Cell & bioscience 20240517 1
<h4>Background</h4>Methylmalonic acidemia (MMA) is a rare inborn error of propionate metabolism caused by deficiency of the mitochondrial methylmalonyl-CoA mutase (MUT) enzyme. As matter of fact, MMA patients manifest impairment of the primary metabolic network with profound damages that involve several cell components, many of which have not been discovered yet. We employed cellular models and patients-derived fibroblasts to refine and uncover new pathologic mechanisms connected with MUT defici ...[more]
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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.
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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
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