Summary of Study ST003555
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR002189. The data can be accessed directly via it's Project DOI: 10.21228/M8P54B This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.
| Study ID | ST003555 |
| Study Title | Mitochondrial dysfunction is a driver of cardiac complications in PGM1-CDG with implications for therapy |
| Study Summary | Phosphoglucomutase 1 (PGM1) plays a crucial role in linking glycolysis, glycogen metabolism, and glycosylation. Pathogenic variants in PGM1 cause a complex multisystem disease, associated with congenital disorder of glycosylation (PGM1-CDG) and lethal cardiac complications. While treatments exist for the glycosylation defect in PGM1-CDG, the cardiac symptoms persist. To investigate the cardiac-specific impact of PGM1 deficiency, we developed human-induced pluripotent stem cell-derived cardiomyocytes (iCMs) from PGM1-CDG individuals. By leveraging omics technologies, we report on significantly reduced beating capacity and widespread molecular alterations linked to mitochondrial dysfunction and energy failure in PGM1-deficient iCMs. Here, we performed tracer metabolomics experiments to understand metabolic rewiring resulting in cardiac failure in PGM1-CDG. By leveraging omics technologies, we report on significantly reduced beating capacity and widespread molecular alterations linked to mitochondrial dysfunction and energy failure in PGM1-deficient iCMs. Tracer metabolomics showed rewiring of glucose metabolism and depletion of ATP, in line with mitochondrial dysfunction assessed by mitochondrial stress tests. Moreover, in-silico drug repurposing identified candidates for treating the cardiac complications of PGM1 deficiency. Our findings unveil a cardiac-specific pathomechanism in PGM1 deficiency and propose crucially needed therapeutic strategies targeting heart failure in PGM1-CDG. |
| Institute | Mayo Clinic |
| Last Name | Radenkovic |
| First Name | Silvia |
| Address | 200 2nd Ave SW Rochester MN, USA |
| silradenkovic@gmail.com | |
| Phone | 507(77) 6-6107 |
| Submit Date | 2024-11-03 |
| Raw Data Available | Yes |
| Raw Data File Type(s) | mzML |
| Analysis Type Detail | LC-MS |
| Release Date | 2025-11-03 |
| Release Version | 1 |
Select appropriate tab below to view additional metadata details:
Project:
| Project ID: | PR002189 |
| Project DOI: | doi: 10.21228/M8P54B |
| Project Title: | Mitochondrial dysfunction is a driver of cardiac complications in PGM1-CDG with implications for therapy |
| Project Summary: | Phosphoglucomutase 1 (PGM1) plays a crucial role in linking glycolysis, glycogen metabolism, and glycosylation. Pathogenic variants in PGM1 cause a complex multisystem disease, associated with congenital disorder of glycosylation (PGM1-CDG) and lethal cardiac complications. While treatments exist for the glycosylation defect in PGM1-CDG, the cardiac symptoms persist. To investigate the cardiac-specific impact of PGM1 deficiency, we developed human-induced pluripotent stem cell-derived cardiomyocytes (iCMs) from PGM1-CDG individuals. |
| Institute: | Mayo Clinic |
| Last Name: | Radenkovic |
| First Name: | Silvia |
| Address: | 200 2nd Ave SW Rochester MN |
| Email: | silradenkovic@gmail.com |
| Phone: | 507(77) 6-6107 |
| Funding Source: | NIH |
Subject:
| Subject ID: | SU003684 |
| Subject Type: | Cultured cells |
| Subject Species: | Homo sapiens |
| Taxonomy ID: | 9606 |
| Genotype Strain: | WT/PGM1 deficient |
| Age Or Age Range: | 3-25 |
| Gender: | Male and female |
| Cell Strain Details: | iPSC-derived cardiomyocytes |
| Species Group: | Mammals |
Factors:
Subject type: Cultured cells; Subject species: Homo sapiens (Factor headings shown in green)
| mb_sample_id | local_sample_id | Genotype |
|---|---|---|
| SA388501 | CR16 | Medium |
| SA388502 | CR15 | Medium |
| SA388503 | CR02 | PGM1 |
| SA388504 | CR12 | PGM1 |
| SA388505 | CR11 | PGM1 |
| SA388506 | CR10 | PGM1 |
| SA388507 | CR01 | PGM1 |
| SA388508 | CR08 | PGM1 |
| SA388509 | CR03 | PGM1 |
| SA388510 | CR09 | PGM1 |
| SA388511 | CR07 | WT |
| SA388512 | CR06 | WT |
| SA388513 | CR05 | WT |
| SA388514 | CR13 | WT |
| SA388515 | CR14 | WT |
| SA388516 | CR04 | WT |
| Showing results 1 to 16 of 16 |
Collection:
| Collection ID: | CO003677 |
| Collection Summary: | iCardiomyocytes were prepared from iPSC according to previously established protocols. Briefly, iPSC were plated, on day 1 the medium was changed to medium containing CHIR inhibitor and B27 minus insulin supplement. The next day, medium without CHIR was added, and the following day as well, to gradually decrease CHIR concentration. On the 4th day, the medium was changed and medium containing IWP2 inhibitor was added. After 2 days, the medium was removed and medium containing no inhibitors was added. Once the beating was observed, medium containing B27 supplement with insulin was added. Cells were collected at day 15. For metabolomics, cells were replated, and medium containing U-13 glucose or normal glucose was added and cells were incubated for 48h. iCardiomyocytes were collected by scraping from the well. Medium was removed, the cells were washed with ice-cold saline solution, then, extraction buffer containing ice-cold 80% Methanol and internal standard (d27 myristic acid) was added. Cells were incubated for 2 min with extraction buffer and then scraped. The cells together with extraction buffer were transferred to a cold eppendorf and stored at -80C before further processing. |
| Sample Type: | iPSC-derived cardiomyocytes (iCardiomyocytes) |
| Volumeoramount Collected: | 120-160 microL |
| Storage Conditions: | -80℃ |
Treatment:
| Treatment ID: | TR003693 |
| Treatment Summary: | NA |
Sample Preparation:
| Sampleprep ID: | SP003691 |
| Sampleprep Summary: | Briefly, after collection, the samples were centrifuged at 15,000 rpm, 4 °C, for 20 min. The liquid phase was transferred to an MS vial and used for LC/MS. The pellet was used to determine protein content. |
| Processing Storage Conditions: | -80℃ |
| Extract Storage: | -80℃ |
Chromatography:
| Chromatography ID: | CH004438 |
| Chromatography Summary: | C18 iP REVERSE PHASE |
| Instrument Name: | Waters Acquity |
| Column Name: | Waters ACQUITY UPLC HSS T3 (150 x 2.1mm,1.8um) |
| Column Temperature: | 40 |
| Flow Gradient: | The gradient started with 5% of solvent B and 95% solvent A and remained at 5% B until 2 min post injection. A linear gradient to 37% B was carried out until 7 min and increased to 41% until 14 min. Between 14 and 26 minutes the gradient increased to 95% of B and remained at 95% B for 4 minutes. At 30 min the gradient returned to 5% B. The chromatography was stopped at 40 min |
| Flow Rate: | 0.25 mL/min |
| Solvent A: | 100% water; 10mM tributylamine; 15mM acetic acid |
| Solvent B: | 100% methanol |
| Chromatography Type: | Reversed phase |
Analysis:
| Analysis ID: | AN005844 |
| Analysis Type: | MS |
| Chromatography ID: | CH004438 |
| Num Factors: | 3 |
| Num Metabolites: | 91 |
| Units: | AUC |
