Summary of Study ST002068
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 PR001310. The data can be accessed directly via it's Project DOI: 10.21228/M8CT43 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 | ST002068 |
Study Title | Mutant CHCHD10 causes an extensive metabolic rewiring that precedes OXPHOS dysfunction in a murine model of mitochondrial cardiomyopathy |
Study Summary | Mitochondrial cardiomyopathies are fatal diseases, with no effective treatment. Alterations of heart mitochondrial function activate the mitochondrial integrated stress response (ISRmt), a transcriptional program affecting cell metabolism, mitochondrial biogenesis, and proteostasis. In humans, mutations in CHCHD10, a mitochondrial protein with unknown function, were recently associated with dominant multi-system mitochondrial diseases, whose pathogenic mechanisms remain to be elucidated. Here, in CHCHD10 knock-in mutant mice, we identify an extensive cardiac metabolic rewiring triggered by proteotoxic ISRmt. The stress response arises early on, before the onset of bioenergetic impairments, triggering a switch from oxidative to glycolytic metabolism, enhancement of transsulfuration and one carbon (1C) metabolism, and widespread metabolic imbalance. In parallel, increased NADPH oxidases elicit antioxidant responses leading to heme depletion. As the disease progresses, the adaptive metabolic stress response fails, resulting in fatal cardiomyopathy. Our findings suggest that early interventions to counteract metabolic imbalance could ameliorate mitochondrial cardiomyopathy associated with proteotoxic ISRmt. |
Institute | Weill Cornell Medicine |
Last Name | Southwell |
First Name | Nneka |
Address | 407 E 61st St |
nns4001@med.cornell.edu | |
Phone | 646-962-8172 |
Submit Date | 2022-01-27 |
Raw Data Available | Yes |
Raw Data File Type(s) | mzXML |
Analysis Type Detail | LC-MS |
Release Date | 2022-02-14 |
Release Version | 1 |
Select appropriate tab below to view additional metadata details:
Project:
Project ID: | PR001310 |
Project DOI: | doi: 10.21228/M8CT43 |
Project Title: | Mutant CHCHD10 causes an extensive metabolic rewiring that precedes OXPHOS dysfunction in a murine model of mitochondrial cardiomyopathy |
Project Summary: | Mitochondrial cardiomyopathies are fatal diseases, with no effective treatment. Alterations of heart mitochondrial function activate the mitochondrial integrated stress response (ISRmt), a transcriptional program affecting cell metabolism, mitochondrial biogenesis, and proteostasis. In humans, mutations in CHCHD10, a mitochondrial protein with unknown function, were recently associated with dominant multi-system mitochondrial diseases, whose pathogenic mechanisms remain to be elucidated. Here, in CHCHD10 knock-in mutant mice, we identify an extensive cardiac metabolic rewiring triggered by proteotoxic ISRmt. The stress response arises early on, before the onset of bioenergetic impairments, triggering a switch from oxidative to glycolytic metabolism, enhancement of transsulfuration and one carbon (1C) metabolism, and widespread metabolic imbalance. In parallel, increased NADPH oxidases elicit antioxidant responses leading to heme depletion. As the disease progresses, the adaptive metabolic stress response fails, resulting in fatal cardiomyopathy. Our findings suggest that early interventions to counteract metabolic imbalance could ameliorate mitochondrial cardiomyopathy associated with proteotoxic ISRmt. |
Institute: | Weill Cornell Medicine |
Last Name: | Southwell |
First Name: | Nneka |
Address: | 407 E 61st St |
Email: | nns4001@med.cornell.edu |
Phone: | 646-962-8172 |
Subject:
Subject ID: | SU002150 |
Subject Type: | Mammal |
Subject Species: | Mus musculus |
Taxonomy ID: | 10090 |
Species Group: | Mammals |
Factors:
Subject type: Mammal; Subject species: Mus musculus (Factor headings shown in green)
mb_sample_id | local_sample_id | Genotype | Sex | Age (d) |
---|---|---|---|---|
SA194656 | S125dMut_9 | CHCHD10 S55L+/- | F | 125 |
SA194657 | S125dMut_10 | CHCHD10 S55L+/- | F | 125 |
SA194658 | S125dMut_7 | CHCHD10 S55L+/- | F | 125 |
SA194659 | S125dMut_6 | CHCHD10 S55L+/- | F | 125 |
SA194660 | S225dMut_13 | CHCHD10 S55L+/- | F | 225 |
SA194661 | S225dMut_16 | CHCHD10 S55L+/- | F | 225 |
SA194662 | S75dMut_1 | CHCHD10 S55L+/- | F | 75 |
SA194663 | S75dMut_2 | CHCHD10 S55L+/- | F | 75 |
SA194664 | S125dMut_11 | CHCHD10 S55L+/- | M | 125 |
SA194665 | S125dMut_8 | CHCHD10 S55L+/- | M | 125 |
SA194666 | S225dMut_14 | CHCHD10 S55L+/- | M | 225 |
SA194667 | S225dMut_12 | CHCHD10 S55L+/- | M | 225 |
SA194668 | S225dMut_15 | CHCHD10 S55L+/- | M | 225 |
SA194669 | S75dMut_4 | CHCHD10 S55L+/- | M | 75 |
SA194670 | S75dMut_3 | CHCHD10 S55L+/- | M | 75 |
SA194671 | S75dMut_5 | CHCHD10 S55L+/- | M | 75 |
SA194672 | S125dCtrl_8 | WT | F | 125 |
SA194673 | S125dCtrl_6 | WT | F | 125 |
SA194674 | S225dCtrl_13 | WT | F | 225 |
SA194675 | S225dCtrl_12 | WT | F | 225 |
SA194676 | S75dCtrl_3 | WT | F | 75 |
SA194677 | S75dCtrl_2 | WT | F | 75 |
SA194678 | S125dCtrl_9 | WT | M | 125 |
SA194679 | S125dCtrl_10 | WT | M | 125 |
SA194680 | S125dCtrl_7 | WT | M | 125 |
SA194681 | S125dCtrl_11 | WT | M | 125 |
SA194682 | S225dCtrl_14 | WT | M | 225 |
SA194683 | S225dCtrl_16 | WT | M | 225 |
SA194684 | S225dCtrl_15 | WT | M | 225 |
SA194685 | S75dCtrl_4 | WT | M | 75 |
SA194686 | S75dCtrl_5 | WT | M | 75 |
SA194687 | S75dCtrl_1 | WT | M | 75 |
Showing results 1 to 32 of 32 |
Collection:
Collection ID: | CO002143 |
Collection Summary: | Murine heart tissue was excised and snap frozen in liquid N2. |
Sample Type: | Heart |
Treatment:
Treatment ID: | TR002162 |
Treatment Summary: | N/A |
Sample Preparation:
Sampleprep ID: | SP002156 |
Sampleprep Summary: | 15 mg of cardiac tissue was homogenized in 80% methanol (Sigma) using Tissue Tearer (BioSpec) on dry ice. Samples were incubated at -80ºC for 4 hours. Homogenates were then centrifuged at 14,000 rfc for 20 min at 4ºC. The supernatant was extracted and stored at -80ºC for mass spectroscopy (Weill Cornell Medicine Meyer Cancer Center Proteomics & Metabolomics Core Facility). Peak intensities for metabolites were screened for missing values and analyzed by using MetaboAnalyst software (version 5.0). |
Combined analysis:
Analysis ID | AN003370 | AN003371 |
---|---|---|
Analysis type | MS | MS |
Chromatography type | HILIC | HILIC |
Chromatography system | Thermo Vanquish | Thermo Vanquish |
Column | SeQuant ZIC-pHILIC (150 x 2.1mm,5um) | SeQuant ZIC-pHILIC (150 x 2.1mm,5um) |
MS Type | ESI | ESI |
MS instrument type | Orbitrap | Orbitrap |
MS instrument name | Thermo Q Exactive Orbitrap | Thermo Q Exactive Orbitrap |
Ion Mode | POSITIVE | NEGATIVE |
Units | Peak Intensity | Peak Intensity |
Chromatography:
Chromatography ID: | CH002492 |
Instrument Name: | Thermo Vanquish |
Column Name: | SeQuant ZIC-pHILIC (150 x 2.1mm,5um) |
Chromatography Type: | HILIC |
MS:
MS ID: | MS003137 |
Analysis ID: | AN003370 |
Instrument Name: | Thermo Q Exactive Orbitrap |
Instrument Type: | Orbitrap |
MS Type: | ESI |
MS Comments: | - |
Ion Mode: | POSITIVE |
MS ID: | MS003138 |
Analysis ID: | AN003371 |
Instrument Name: | Thermo Q Exactive Orbitrap |
Instrument Type: | Orbitrap |
MS Type: | ESI |
MS Comments: | - |
Ion Mode: | NEGATIVE |