Summary of Study ST003128

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 PR001944. The data can be accessed directly via it's Project DOI: 10.21228/M8FD9G This work is supported by NIH grant, U2C- DK119886.

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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.

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Study IDST003128
Study TitleEffect of high fat diet on serum fatty acids, lipidome and metabolome in CHCHD10 mutant mice
Study SummaryMutations in CHCHD10, a mitochondrial protein with undefined functions, are associated with autosomal dominant mitochondrial diseases. Chchd10 knock-in mice harboring a heterozygous S55L mutation (equivalent to human pathogenic S59L) develop a fatal mitochondrial cardiomyopathy caused by CHCHD10 aggregation and proteotoxic mitochondrial integrated stress response (mtISR). In mutant hearts, mtISR is accompanied by a metabolic rewiring characterized by increased reliance on glycolysis rather than fatty acid oxidation. To counteract this metabolic rewiring, heterozygous S55L mice were subjected to chronic high fat diet (HFD) to decrease insulin sensitivity and glucose uptake and enhance fatty acid utilization in the heart. HFD ameliorated the ventricular dysfunction of mutant hearts and significantly extended the survival of mutant female mice affected by severe pregnancy-induced cardiomyopathy. Gene expression profiles confirmed that HFD increased fatty acid utilization and ameliorated cardiomyopathy markers. Importantly, HFD also decreased accumulation of aggregated CHCHD10 in the S55L heart, suggesting activation of quality control mechanisms. Overall, our findings indicate that metabolic therapy can be effective in mitochondrial cardiomyopathies associated with proteotoxic stress.
Institute
Weill Cornell Medicine
Last NameSouthwell
First NameNneka
Address407 E 61st St
Emailnns4001@med.cornell.edu
Phone646-962-8172
Submit Date2024-03-06
Raw Data AvailableYes
Raw Data File Type(s)raw(Thermo)
Analysis Type DetailLC-MS
Release Date2024-03-26
Release Version1
Nneka Southwell Nneka Southwell
https://dx.doi.org/10.21228/M8FD9G
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Project:

Project ID:PR001944
Project DOI:doi: 10.21228/M8FD9G
Project Title:High fat diet ameliorates mitochondrial cardiomyopathy in CHCHD10 mutant mice
Project Summary:Mutations in CHCHD10, a mitochondrial protein with undefined functions, are associated with autosomal dominant mitochondrial diseases. Chchd10 knock-in mice harboring a heterozygous S55L mutation (equivalent to human pathogenic S59L) develop a fatal mitochondrial cardiomyopathy caused by CHCHD10 aggregation and proteotoxic mitochondrial integrated stress response (mtISR). In mutant hearts, mtISR is accompanied by a metabolic rewiring characterized by increased reliance on glycolysis rather than fatty acid oxidation. To counteract this metabolic rewiring, heterozygous S55L mice were subjected to chronic high fat diet (HFD) to decrease insulin sensitivity and glucose uptake and enhance fatty acid utilization in the heart. HFD ameliorated the ventricular dysfunction of mutant hearts and significantly extended the survival of mutant female mice affected by severe pregnancy-induced cardiomyopathy. Gene expression profiles confirmed that HFD increased fatty acid utilization and ameliorated cardiomyopathy markers. Importantly, HFD also decreased accumulation of aggregated CHCHD10 in the S55L heart, suggesting activation of quality control mechanisms. Overall, our findings indicate that metabolic therapy can be effective in mitochondrial cardiomyopathies associated with proteotoxic stress.
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:SU003245
Subject Type:Mammal
Subject Species:Mus musculus
Taxonomy ID:10090

Factors:

Subject type: Mammal; Subject species: Mus musculus (Factor headings shown in green)

mb_sample_id local_sample_id Sample source
SA338967SL_HetCD_6Serum | Genotype:CHCHD10 S55L Het | Treatment:Control Diet | Age (d):250 | Sex:F
SA338968S_HetCD_2Serum | Genotype:CHCHD10 S55L Het | Treatment:Control Diet | Age (d):250 | Sex:F
SA338969SL_HetCD_3Serum | Genotype:CHCHD10 S55L Het | Treatment:Control Diet | Age (d):250 | Sex:F
SA338970SP_HetCD_1Serum | Genotype:CHCHD10 S55L Het | Treatment:Control Diet | Age (d):250 | Sex:F
SA338971SL_HetCD_5Serum | Genotype:CHCHD10 S55L Het | Treatment:Control Diet | Age (d):250 | Sex:F
SA338972SL_HetCD_2Serum | Genotype:CHCHD10 S55L Het | Treatment:Control Diet | Age (d):250 | Sex:F
SA338973SL_HetCD_1Serum | Genotype:CHCHD10 S55L Het | Treatment:Control Diet | Age (d):250 | Sex:F
SA338974SL_HetCD_4Serum | Genotype:CHCHD10 S55L Het | Treatment:Control Diet | Age (d):250 | Sex:F
SA338975SP_HetCD_6Serum | Genotype:CHCHD10 S55L Het | Treatment:Control Diet | Age (d):250 | Sex:F
SA338976S_HetCD_1Serum | Genotype:CHCHD10 S55L Het | Treatment:Control Diet | Age (d):250 | Sex:F
SA338977S_HetCD_5Serum | Genotype:CHCHD10 S55L Het | Treatment:Control Diet | Age (d):250 | Sex:F
SA338978S_HetCD_6Serum | Genotype:CHCHD10 S55L Het | Treatment:Control Diet | Age (d):250 | Sex:F
SA338979SP_HetCD_2Serum | Genotype:CHCHD10 S55L Het | Treatment:Control Diet | Age (d):250 | Sex:F
SA338980S_HetCD_4Serum | Genotype:CHCHD10 S55L Het | Treatment:Control Diet | Age (d):250 | Sex:F
SA338981S_HetCD_3Serum | Genotype:CHCHD10 S55L Het | Treatment:Control Diet | Age (d):250 | Sex:F
SA338982SP_HetCD_5Serum | Genotype:CHCHD10 S55L Het | Treatment:Control Diet | Age (d):250 | Sex:F
SA338983SP_HetCD_4Serum | Genotype:CHCHD10 S55L Het | Treatment:Control Diet | Age (d):250 | Sex:F
SA338984SP_HetCD_3Serum | Genotype:CHCHD10 S55L Het | Treatment:Control Diet | Age (d):250 | Sex:F
SA338985SL_HetHFD_2Serum | Genotype:CHCHD10 S55L Het | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA338986SL_HetHFD_5Serum | Genotype:CHCHD10 S55L Het | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA338987SL_HetHFD_6Serum | Genotype:CHCHD10 S55L Het | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA338988SL_HetHFD_4Serum | Genotype:CHCHD10 S55L Het | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA338989SL_HetHFD_3Serum | Genotype:CHCHD10 S55L Het | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA338990SP_HetHFD_1Serum | Genotype:CHCHD10 S55L Het | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA338991SL_HetHFD_1Serum | Genotype:CHCHD10 S55L Het | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA338992SP_HetHFD_4Serum | Genotype:CHCHD10 S55L Het | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA338993S_HetHFD_3Serum | Genotype:CHCHD10 S55L Het | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA338994SP_HetHFD_2Serum | Genotype:CHCHD10 S55L Het | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA338995S_HetHFD_4Serum | Genotype:CHCHD10 S55L Het | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA338996S_HetHFD_5Serum | Genotype:CHCHD10 S55L Het | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA338997S_HetHFD_2Serum | Genotype:CHCHD10 S55L Het | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA338998S_HetHFD_1Serum | Genotype:CHCHD10 S55L Het | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA338999SP_HetHFD_3Serum | Genotype:CHCHD10 S55L Het | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA339000SP_HetHFD_5Serum | Genotype:CHCHD10 S55L Het | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA339001SP_HetHFD_6Serum | Genotype:CHCHD10 S55L Het | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA339002S_HetHFD_6Serum | Genotype:CHCHD10 S55L Het | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA339003SP_WTCD_4Serum | Genotype:WT | Treatment:Control Diet | Age (d):250 | Sex:F
SA339004SP_WTCD_1Serum | Genotype:WT | Treatment:Control Diet | Age (d):250 | Sex:F
SA339005SP_WTCD_2Serum | Genotype:WT | Treatment:Control Diet | Age (d):250 | Sex:F
SA339006SP_WTCD_3Serum | Genotype:WT | Treatment:Control Diet | Age (d):250 | Sex:F
SA339007SP_WTCD_5Serum | Genotype:WT | Treatment:Control Diet | Age (d):250 | Sex:F
SA339008SP_WTCD_6Serum | Genotype:WT | Treatment:Control Diet | Age (d):250 | Sex:F
SA339009SL_WTCD_1Serum | Genotype:WT | Treatment:Control Diet | Age (d):250 | Sex:F
SA339010SL_WTCD_2Serum | Genotype:WT | Treatment:Control Diet | Age (d):250 | Sex:F
SA339011SL_WTCD_3Serum | Genotype:WT | Treatment:Control Diet | Age (d):250 | Sex:F
SA339012S_WTCD_2Serum | Genotype:WT | Treatment:Control Diet | Age (d):250 | Sex:F
SA339013S_WTCD_3Serum | Genotype:WT | Treatment:Control Diet | Age (d):250 | Sex:F
SA339014S_WTCD_5Serum | Genotype:WT | Treatment:Control Diet | Age (d):250 | Sex:F
SA339015S_WTCD_4Serum | Genotype:WT | Treatment:Control Diet | Age (d):250 | Sex:F
SA339016S_WTCD_6Serum | Genotype:WT | Treatment:Control Diet | Age (d):250 | Sex:F
SA339017SL_WTCD_4Serum | Genotype:WT | Treatment:Control Diet | Age (d):250 | Sex:F
SA339018SL_WTCD_5Serum | Genotype:WT | Treatment:Control Diet | Age (d):250 | Sex:F
SA339019S_WTCD_1Serum | Genotype:WT | Treatment:Control Diet | Age (d):250 | Sex:F
SA339020SL_WTCD_6Serum | Genotype:WT | Treatment:Control Diet | Age (d):250 | Sex:F
SA339021SP_WTHFD_6Serum | Genotype:WT | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA339022SP_WTHFD_5Serum | Genotype:WT | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA339023SP_WTHFD_1Serum | Genotype:WT | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA339024SP_WTHFD_3Serum | Genotype:WT | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA339025SP_WTHFD_2Serum | Genotype:WT | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA339026SP_WTHFD_4Serum | Genotype:WT | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA339027S_WTHFD_3Serum | Genotype:WT | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA339028SL_WTHFD_2Serum | Genotype:WT | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA339029SL_WTHFD_6Serum | Genotype:WT | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA339030SL_WTHFD_5Serum | Genotype:WT | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA339031SL_WTHFD_4Serum | Genotype:WT | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA339032SL_WTHFD_1Serum | Genotype:WT | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA339033S_WTHFD_6Serum | Genotype:WT | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA339034S_WTHFD_2Serum | Genotype:WT | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA339035SL_WTHFD_3Serum | Genotype:WT | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA339036S_WTHFD_4Serum | Genotype:WT | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA339037S_WTHFD_5Serum | Genotype:WT | Treatment:High Fat Diet | Age (d):250 | Sex:F
SA339038S_WTHFD_1Serum | Genotype:WT | Treatment:High Fat Diet | Age (d):250 | Sex:F
Showing results 1 to 72 of 72

Collection:

Collection ID:CO003238
Collection Summary:Blood was collected by cheek bleeds into serum separator tubes. Serum was separated after 30 minutes of clotting at room temperature and centrifugation at 2000xg for 15 min.
Sample Type:Blood (serum)

Treatment:

Treatment ID:TR003254
Treatment Summary:CHCHD10 WT and CHCHD10 S55L heterozygous mice were treated with either a control diet (70% Carbohydrate, 20% Protein, 10% Fat) or High Fat Diet (60% Fat, 20% Protein, 20% Carbohydrate).

Sample Preparation:

Sampleprep ID:SP003252
Sampleprep Summary:Untargeted and targeted metabolomics: Serum metabolites were extracted with 80% methanol. The extracts were clarified by centrifugation at 15,000 g for 10 min. The supernatant was collected and dried down using a SpeedVac. For lipidomics analyses: 180 µl of 90% isopropanol was added to 20 µl serum. Samples were vortexed for 2 min, sonicated for 1 min using a probe sonicator and centrifuged at 15,000 g for 10 min. The supernatant was collected and dried down using a SpeedVac. The dried samples were reconstituted using acetonitrile/isopropanol/water 65:30:5 containing stable isotope labeled internal lipid standards (Splash Lipidomix, Avanti Polar Lipids) prior to LC-MS analysis. Free Fatty Acids: Free fatty acids were extracted from serum using 90% methanol (LC/MS grade, Thermo Scientific). The extracts were clarified by centrifugation at 15,000 g for 10 min. The supernatant was collected and dried down using a SpeedVac. The dried sample was reconstituted using 50% methanol prior to LC-MS analysis.

Combined analysis:

Analysis ID AN005128 AN005129 AN005130
Analysis type MS MS MS
Chromatography type HILIC Reversed phase Reversed phase
Chromatography system Thermo Vanquish Thermo Vanquish Thermo Vanquish
Column SeQuant ZIC-pHILIC (150 x 2.1mm, 5um) Imtakt Cadenza CD-C18 (150 x 2.1 mm, 3um) Imtakt Cadenza CD-C18 (150 x 2.1 mm, 3um)
MS Type ESI ESI ESI
MS instrument type Orbitrap Orbitrap Orbitrap
MS instrument name Thermo Q Exactive Orbitrap Thermo Q Exactive Orbitrap Thermo Q Exactive Orbitrap
Ion Mode UNSPECIFIED NEGATIVE POSITIVE
Units Peak Intensity Peak Intensity Peak Intensity

Chromatography:

Chromatography ID:CH003880
Chromatography Summary:Serum targeted and untargeted metabolomics
Methods Filename:Serum_MS_and_Data_Analysis.pdf
Instrument Name:Thermo Vanquish
Column Name:SeQuant ZIC-pHILIC (150 x 2.1mm, 5um)
Column Temperature:35
Flow Gradient:85% to 30% A in 20 min followed by a wash with 30% A and re-equilibration at 85% A
Flow Rate:150 µl/min
Solvent A:100% acetonitrile
Solvent B:100% water; 0.1% ammonium hydroxide; 20 mM ammonium acetate
Chromatography Type:HILIC
  
Chromatography ID:CH003881
Chromatography Summary:Serum free fatty acids
Methods Filename:Serum_MS_and_Data_Analysis.pdf
Instrument Name:Thermo Vanquish
Column Name:Imtakt Cadenza CD-C18 (150 x 2.1 mm, 3um)
Column Temperature:35
Flow Gradient:0–1.5 min, 50% B; 1.5-3 min, 50-90% B; 3-5.5 min, 90-95% B; 5.5-10 min, 95% B, followed by 5 min of re-equilibration
Flow Rate:150 µl/min
Solvent A:100% water; 5 mM ammonium acetate
Solvent B:85% isopropanol/10% acetonitrile/5% water; 5 mM ammonium acetate
Chromatography Type:Reversed phase
  
Chromatography ID:CH003882
Chromatography Summary:Serum lipidomics
Methods Filename:Serum_MS_and_Data_Analysis.pdf
Instrument Name:Thermo Vanquish
Column Name:Imtakt Cadenza CD-C18 (150 x 2.1 mm, 3um)
Column Temperature:35
Flow Gradient:0–1.5 min, 32% B; 1.5-4 min, 32-45% B; 4-5 min, 45-52% B; 5-8 min, 52-58% B; 8-11 min, 58-66% B; 11-14 min, 66-70% B; 14-18 min, 70-75% B; 21-25 min, isocratic 97% B, 25-25.1 min 97-32% B
Flow Rate:200 µl/min
Solvent A:60% acetonitrile/40% water; 10 mM ammonium formate; 0.1% formic acid
Solvent B:90% isopropanol/10% acetonitrile; 10 mM ammonium formate; 0.1% formic acid
Chromatography Type:Reversed phase

MS:

MS ID:MS004864
Analysis ID:AN005128
Instrument Name:Thermo Q Exactive Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:The MS data was processed using XCalibur 4.1 (Thermo Scientific) to obtain the metabolite signal intensity for relative quantitation. Targeted identification was available for 205 metabolites based on an in-house library established using known chemical standards. Identification required exact mass (within 5ppm) and standard retention times. For untargeted metabolomics, metabolites were identified by mass matching of the MS signal to metabolites in the HMDB database. If multiple metabolites in the database were matched to a certain MS signal, all matched metabolites were grouped into a single identification, and ordered based on the number of references included in the HMDB database (high to low).
Ion Mode:UNSPECIFIED
Analysis Protocol File:Serum_MS_and_Data_Analysis.pdf
  
MS ID:MS004865
Analysis ID:AN005129
Instrument Name:Thermo Q Exactive Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:Identification of free fatty acids was based on accurate masses within 5 ppm and standard retention times from compound standards. Relative quantitation was performed based on MS signal intensities.
Ion Mode:NEGATIVE
Analysis Protocol File:Serum_MS_and_Data_Analysis.pdf
  
MS ID:MS004866
Analysis ID:AN005130
Instrument Name:Thermo Q Exactive Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:A data-dependent mass spectrometric acquisition method was used for lipid identification. In this method, each MS survey scan was followed by up to 10 MS/MS scans performed on the most abundant ions. The LC-MS results were processed using MS-DIAL software (version 4.9) for lipid identification and relative quantitation.
Ion Mode:POSITIVE
Analysis Protocol File:Serum_MS_and_Data_Analysis.pdf
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