{
"METABOLOMICS WORKBENCH":{"STUDY_ID":"ST002872","ANALYSIS_ID":"AN004708","VERSION":"1","CREATED_ON":"09-28-2023"},

"PROJECT":{"PROJECT_TITLE":"Comparative multi-omics analyses of cardiac mitochondrial stress in three mouse models of frataxin deficiency","PROJECT_SUMMARY":"Cardiomyopathy is often fatal in Friedreich Ataxia (FA). However, the FA heart maintains adequate function until disease end stage, suggesting that it can initially adapt to the loss of frataxin (FXN). Conditional knockout mouse models with no Fxn expression show transcriptional and metabolic profiles of cardiomyopathy and mitochondrial integrated stress response (ISRmt). However, ISRmt has not been investigated in models with disease-relevant, partial decrease of FXN. We characterized the heart transcriptomes and metabolomes of three mouse models of partial FXN loss, YG8-800, KIKO-700, and FxnG127V. Few metabolites were significantly changed in YG8-800 mice and did not provide a signature of cardiomyopathy or ISRmt. Instead, several metabolites were altered in FxnG127V and KIKO-700 hearts. Transcriptional changes were found in all models, but differentially expressed genes consistent with cardiomyopathy and ISRmt were only identified in FxnG127V hearts. However, these changes were surprisingly mild even at an advanced age (18-months), despite a severe decrease in FXN levels to 1% of WT. These findings indicate that the mouse heart has extremely low reliance on FXN, highlighting the difficulty in modeling genetically relevant FA cardiomyopathy.","INSTITUTE":"Weill Cornell Medicine","LAST_NAME":"Nicole","FIRST_NAME":"Sayles","ADDRESS":"407 East 61st St, 5th Floor, New York, NY 10065","EMAIL":"nms2009@med.cornell.edu","PHONE":"5167435432","PUBLICATIONS":"https://journals.biologists.com/dmm/article/doi/10.1242/dmm.050114/328282/Comparative-multi-omics-analyses-of-cardiac","DOI":"http://dx.doi.org/10.21228/M8TD9W"},

"STUDY":{"STUDY_TITLE":"Comparative multi-omics analyses of cardiac mitochondrial stress in three mouse models of frataxin deficiency","STUDY_SUMMARY":"Cardiomyopathy is often fatal in Friedreich Ataxia (FA). However, the FA heart maintains adequate function until disease end stage, suggesting that it can initially adapt to the loss of frataxin (FXN). Conditional knockout mouse models with no Fxn expression show transcriptional and metabolic profiles of cardiomyopathy and mitochondrial integrated stress response (ISRmt). However, ISRmt has not been investigated in models with disease-relevant, partial decrease of FXN. We characterized the heart transcriptomes and metabolomes of three mouse models of partial FXN loss, YG8-800, KIKO-700, and FxnG127V. Few metabolites were significantly changed in YG8-800 mice and did not provide a signature of cardiomyopathy or ISRmt. Instead, several metabolites were altered in FxnG127V and KIKO-700 hearts. Transcriptional changes were found in all models, but differentially expressed genes consistent with cardiomyopathy and ISRmt were only identified in FxnG127V hearts. However, these changes were surprisingly mild even at an advanced age (18-months), despite a severe decrease in FXN levels to 1% of WT. These findings indicate that the mouse heart has extremely low reliance on FXN, highlighting the difficulty in modeling genetically relevant FA cardiomyopathy.","INSTITUTE":"Weill Cornell Medicine","LAST_NAME":"Sayles","FIRST_NAME":"Nicole","ADDRESS":"407 East 61st St, 5th Floor, New York, NY 10065","EMAIL":"nms2009@med.cornell.edu","PHONE":"6469628172","SUBMIT_DATE":"2023-02-01"},

"SUBJECT":{"SUBJECT_TYPE":"Mammal","SUBJECT_SPECIES":"Mus musculus","TAXONOMY_ID":"10090"},
"SUBJECT_SAMPLE_FACTORS":[
{
"Subject ID":"-",
"Sample ID":"KOFemale_1030",
"Factors":{"Genotype":"KIKO","Treatment":"KIKO_700 F"},
"Additional sample data":{"RAW_FILE_NAME":"mz_210302_philic_posNeg_NS796_T_KOFemale_1030.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"KOFemale_1059",
"Factors":{"Genotype":"KIKO","Treatment":"KIKO_700 F"},
"Additional sample data":{"RAW_FILE_NAME":"mz_210302_philic_posNeg_NS796_T_KOFemale_1059.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"KOFemale_1061",
"Factors":{"Genotype":"KIKO","Treatment":"KIKO_700 F"},
"Additional sample data":{"RAW_FILE_NAME":"mz_210302_philic_posNeg_NS796_T_KOFemale_1061.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"KOMale_1040",
"Factors":{"Genotype":"KIKO","Treatment":"KIKO_700 M"},
"Additional sample data":{"RAW_FILE_NAME":"mz_210302_philic_posNeg_NS796_T_KOMale_1040.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"KOMale_1042",
"Factors":{"Genotype":"KIKO","Treatment":"KIKO_700 M"},
"Additional sample data":{"RAW_FILE_NAME":"mz_210302_philic_posNeg_NS796_T_KOMale_1042.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"KOMale_1069",
"Factors":{"Genotype":"KIKO","Treatment":"KIKO_700 M"},
"Additional sample data":{"RAW_FILE_NAME":"mz_210302_philic_posNeg_NS796_T_KOMale_1069.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"MUTFemale_340",
"Factors":{"Genotype":"Mutant","Treatment":"G127V F"},
"Additional sample data":{"RAW_FILE_NAME":"mz_210302_philic_posNeg_NS796_T_MUTFemale_340.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"MUTFemale_358",
"Factors":{"Genotype":"Mutant","Treatment":"G127V F"},
"Additional sample data":{"RAW_FILE_NAME":"mz_210302_philic_posNeg_NS796_T_MUTFemale_358.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"MUTFemale_390",
"Factors":{"Genotype":"Mutant","Treatment":"G127V F"},
"Additional sample data":{"RAW_FILE_NAME":"mz_210302_philic_posNeg_NS796_T_MUTFemale_390.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"MUTMale_226",
"Factors":{"Genotype":"Mutant","Treatment":"G127V M"},
"Additional sample data":{"RAW_FILE_NAME":"mz_210302_philic_posNeg_NS796_T_MUTMale_226.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"MUTMale_356",
"Factors":{"Genotype":"Mutant","Treatment":"G127V M"},
"Additional sample data":{"RAW_FILE_NAME":"mz_210302_philic_posNeg_NS796_T_MUTMale_356.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"MUTMale_433",
"Factors":{"Genotype":"Mutant","Treatment":"G127V M"},
"Additional sample data":{"RAW_FILE_NAME":"mz_210302_philic_posNeg_NS796_T_MUTMale_433.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"HeartY8PTgE_50",
"Factors":{"Genotype":"Mutant","Treatment":"YG8-800"},
"Additional sample data":{"RAW_FILE_NAME":"mz_201130_philic_posNeg_HF750_T_HeartY8PTgE_50.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"HeartY8PTgE_94",
"Factors":{"Genotype":"Mutant","Treatment":"YG8-800"},
"Additional sample data":{"RAW_FILE_NAME":"mz_201130_philic_posNeg_HF750_T_HeartY8PTgE_94.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"HeartY8PTgE_96",
"Factors":{"Genotype":"Mutant","Treatment":"YG8-800"},
"Additional sample data":{"RAW_FILE_NAME":"mz_201130_philic_posNeg_HF750_T_HeartY8PTgE_96.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"HeartY8PTgE_99",
"Factors":{"Genotype":"Mutant","Treatment":"YG8-800"},
"Additional sample data":{"RAW_FILE_NAME":"mz_201130_philic_posNeg_HF750_T_HeartY8PTgE_99.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"HeartEX2wt_184",
"Factors":{"Genotype":"Wild-type","Treatment":"Control"},
"Additional sample data":{"RAW_FILE_NAME":"mz_201130_philic_posNeg_HF750_T_HeartEX2wt_184.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"HeartEX2wt_199",
"Factors":{"Genotype":"Wild-type","Treatment":"Control"},
"Additional sample data":{"RAW_FILE_NAME":"mz_201130_philic_posNeg_HF750_T_HeartEX2wt_199.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"HeartEX2wt_51",
"Factors":{"Genotype":"Wild-type","Treatment":"Control"},
"Additional sample data":{"RAW_FILE_NAME":"mz_201130_philic_posNeg_HF750_T_HeartEX2wt_51.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"HeartEX2wt_93",
"Factors":{"Genotype":"Wild-type","Treatment":"Control"},
"Additional sample data":{"RAW_FILE_NAME":"mz_201130_philic_posNeg_HF750_T_HeartEX2wt_93.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"WTFemale_200",
"Factors":{"Genotype":"Wild-type","Treatment":"Control F"},
"Additional sample data":{"RAW_FILE_NAME":"mz_210302_philic_posNeg_NS796_T_WTFemale_200.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"WTFemale_220",
"Factors":{"Genotype":"Wild-type","Treatment":"Control F"},
"Additional sample data":{"RAW_FILE_NAME":"mz_210302_philic_posNeg_NS796_T_WTFemale_220.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"WTFemale_221",
"Factors":{"Genotype":"Wild-type","Treatment":"Control F"},
"Additional sample data":{"RAW_FILE_NAME":"mz_210302_philic_posNeg_NS796_T_WTFemale_221.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"WTMale_204",
"Factors":{"Genotype":"Wild-type","Treatment":"Control M"},
"Additional sample data":{"RAW_FILE_NAME":"mz_210302_philic_posNeg_NS796_T_WTMale_204.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"WTMale_207",
"Factors":{"Genotype":"Wild-type","Treatment":"Control M"},
"Additional sample data":{"RAW_FILE_NAME":"mz_210302_philic_posNeg_NS796_T_WTMale_207.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"WTMale_218",
"Factors":{"Genotype":"Wild-type","Treatment":"Control M"},
"Additional sample data":{"RAW_FILE_NAME":"mz_210302_philic_posNeg_NS796_T_WTMale_218.mzXML"}
}
],
"COLLECTION":{"COLLECTION_SUMMARY":"Mice were anesthetized with pentobarbital. Hearts were extracted, washed in PBS and snap frozen in liquid nitrogen.","SAMPLE_TYPE":"Heart"},

"TREATMENT":{"TREATMENT_SUMMARY":"N/A"},

"SAMPLEPREP":{"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)."},

"CHROMATOGRAPHY":{"INSTRUMENT_NAME":"Thermo Vanquish","COLUMN_NAME":"SeQuant ZIC-pHILIC (150 x 2.1mm, 5um)","COLUMN_TEMPERATURE":"30","FLOW_GRADIENT":"85% to 30% acetonitrile (ACN)","FLOW_RATE":"150 μL/min","SOLVENT_A":"0.1% NH4OH/20 mM CH3COONH4","SOLVENT_B":"100% acetonitrile","CHROMATOGRAPHY_TYPE":"HILIC"},

"ANALYSIS":{"ANALYSIS_TYPE":"MS"},

"MS":{"INSTRUMENT_NAME":"Thermo Q Exactive Orbitrap","INSTRUMENT_TYPE":"Orbitrap","MS_TYPE":"ESI","MS_COMMENTS":"MS acquisition Comments: The Q Exactive was operated in full scan, polarity-switching mode with the following parameters: the spray voltage 3.0 kV, the heated capillary temperature 300 °C, the HESI probe temperature 350 °C, the sheath gas flow 40 units, the auxiliary gas flow 15 units. MS data acquisition was performed in the m/z range of 70–1,000, with 70,000 resolution (at 200 m/z). Data processing Comments: The MS data was processed using XCalibur 4.1 (Thermo Scientific) to extract the metabolite signal intensity for relative quantitation. Metabolites were identified using an in-house library established using chemical standards. Identification required exact mass (within 5ppm) and standard retention times. Software/procedures used for feature assignments: The MS data was processed using XCalibur 4.1 (Thermo Scientific) to extract the metabolite signal intensity for relative quantitation. Metabolites were identified using an in-house library established using chemical standards. Identification required exact mass (within 5ppm) and standard retention times.","ION_MODE":"POSITIVE"},

"MS_METABOLITE_DATA":{
"Units":"Peak intensity",

"Data":[{"Metabolite":"1-Methyladenosine","KOFemale_1030":"6371.4340","KOFemale_1059":"","KOFemale_1061":"3350.9100","KOMale_1040":"3215.9160","KOMale_1042":"4183.0560","KOMale_1069":"3708.9950","MUTFemale_340":"6496.9430","MUTFemale_358":"8198.4480","MUTFemale_390":"","MUTMale_226":"","MUTMale_356":"3184.9640","MUTMale_433":"","HeartY8PTgE_50":"4619.2540","HeartY8PTgE_94":"2514.3830","HeartY8PTgE_96":"","HeartY8PTgE_99":"","HeartEX2wt_184":"","HeartEX2wt_199":"","HeartEX2wt_51":"2034.6080","HeartEX2wt_93":"","WTFemale_200":"9367.7800","WTFemale_220":"","WTFemale_221":"5196.0630","WTMale_204":"","WTMale_207":"","WTMale_218":"2959.0380"},{"Metabolite":"1-Methylnicotinamide","KOFemale_1030":"1213580.0000","KOFemale_1059":"1120997.0000","KOFemale_1061":"1515973.0000","KOMale_1040":"554540.8000","KOMale_1042":"1469390.0000","KOMale_1069":"1552967.0000","MUTFemale_340":"2223429.0000","MUTFemale_358":"2330811.0000","MUTFemale_390":"1155010.0000","MUTMale_226":"886342.0000","MUTMale_356":"1325493.0000","MUTMale_433":"542208.8000","HeartY8PTgE_50":"813349.1000","HeartY8PTgE_94":"1966464.0000","HeartY8PTgE_96":"1517031.0000","HeartY8PTgE_99":"1704972.0000","HeartEX2wt_184":"2020423.0000","HeartEX2wt_199":"920371.9000","HeartEX2wt_51":"1263208.0000","HeartEX2wt_93":"896104.1000","WTFemale_200":"1965060.0000","WTFemale_220":"1799170.0000","WTFemale_221":"1985319.0000","WTMale_204":"1941939.0000","WTMale_207":"1227933.0000","WTMale_218":"1652470.0000"},{"Metabolite":"2-Hydroxycaproic acid","KOFemale_1030":"231237.1000","KOFemale_1059":"350119.7000","KOFemale_1061":"165731.8000","KOMale_1040":"271175.4000","KOMale_1042":"181324.0000","KOMale_1069":"284006.0000","MUTFemale_340":"333397.0000","MUTFemale_358":"438849.8000","MUTFemale_390":"239456.7000","MUTMale_226":"177465.2000","MUTMale_356":"331904.9000","MUTMale_433":"237772.6000","HeartY8PTgE_50":"533336.8000","HeartY8PTgE_94":"631044.9000","HeartY8PTgE_96":"761824.6000","HeartY8PTgE_99":"296567.4000","HeartEX2wt_184":"372807.6000","HeartEX2wt_199":"306374.0000","HeartEX2wt_51":"570770.8000","HeartEX2wt_93":"306086.3000","WTFemale_200":"313419.1000","WTFemale_220":"289232.0000","WTFemale_221":"199870.8000","WTMale_204":"240154.5000","WTMale_207":"221469.3000","WTMale_218":"290833.4000"},{"Metabolite":"2-Hydroxyvaleric acid","KOFemale_1030":"431935.3000","KOFemale_1059":"482510.8000","KOFemale_1061":"409608.9000","KOMale_1040":"831165.7000","KOMale_1042":"1213559.0000","KOMale_1069":"1136692.0000","MUTFemale_340":"576753.2000","MUTFemale_358":"3003260.0000","MUTFemale_390":"421157.6000","MUTMale_226":"665622.7000","MUTMale_356":"1268743.0000","MUTMale_433":"900542.2000","HeartY8PTgE_50":"820002.3000","HeartY8PTgE_94":"474613.7000","HeartY8PTgE_96":"661766.4000","HeartY8PTgE_99":"302105.9000","HeartEX2wt_184":"540147.5000","HeartEX2wt_199":"1043311.0000","HeartEX2wt_51":"1455151.0000","HeartEX2wt_93":"404347.7000","WTFemale_200":"646614.4000","WTFemale_220":"469057.1000","WTFemale_221":"469882.2000","WTMale_204":"1293313.0000","WTMale_207":"1293068.0000","WTMale_218":"1582150.0000"},{"Metabolite":"3-Hydroxymethylglutaric acid","KOFemale_1030":"237620.1000","KOFemale_1059":"258514.4000","KOFemale_1061":"233382.9000","KOMale_1040":"260759.0000","KOMale_1042":"246235.0000","KOMale_1069":"353795.7000","MUTFemale_340":"560233.8000","MUTFemale_358":"3079722.0000","MUTFemale_390":"241783.5000","MUTMale_226":"272599.1000","MUTMale_356":"587475.3000","MUTMale_433":"268253.2000","HeartY8PTgE_50":"521850.8000","HeartY8PTgE_94":"755437.4000","HeartY8PTgE_96":"655307.0000","HeartY8PTgE_99":"474119.8000","HeartEX2wt_184":"655850.9000","HeartEX2wt_199":"514492.4000","HeartEX2wt_51":"558306.7000","HeartEX2wt_93":"483746.3000","WTFemale_200":"257588.2000","WTFemale_220":"258197.5000","WTFemale_221":"265941.6000","WTMale_204":"302010.9000","WTMale_207":"245445.0000","WTMale_218":"257727.3000"},{"Metabolite":"3-Methylhistidine","KOFemale_1030":"4624852.0000","KOFemale_1059":"3215564.0000","KOFemale_1061":"2213987.0000","KOMale_1040":"5164323.0000","KOMale_1042":"2787693.0000","KOMale_1069":"4346638.0000","MUTFemale_340":"2610372.0000","MUTFemale_358":"7248194.0000","MUTFemale_390":"2189878.0000","MUTMale_226":"3017856.0000","MUTMale_356":"2452300.0000","MUTMale_433":"1258715.0000","HeartY8PTgE_50":"13975970.0000","HeartY8PTgE_94":"26620630.0000","HeartY8PTgE_96":"21015900.0000","HeartY8PTgE_99":"11110500.0000","HeartEX2wt_184":"28536590.0000","HeartEX2wt_199":"14547520.0000","HeartEX2wt_51":"33194880.0000","HeartEX2wt_93":"13052930.0000","WTFemale_200":"4304231.0000","WTFemale_220":"3504596.0000","WTFemale_221":"4940022.0000","WTMale_204":"4551849.0000","WTMale_207":"3026281.0000","WTMale_218":"5185561.0000"},{"Metabolite":"3-Phosphoglyceric acid","KOFemale_1030":"112428.3000","KOFemale_1059":"92212.0500","KOFemale_1061":"79566.9600","KOMale_1040":"74355.9900","KOMale_1042":"91264.1100","KOMale_1069":"172092.5000","MUTFemale_340":"640232.2000","MUTFemale_358":"353588.4000","MUTFemale_390":"67011.0900","MUTMale_226":"196454.4000","MUTMale_356":"120919.9000","MUTMale_433":"47166.6800","HeartY8PTgE_50":"2595904.0000","HeartY8PTgE_94":"5553642.0000","HeartY8PTgE_96":"4817855.0000","HeartY8PTgE_99":"4385314.0000","HeartEX2wt_184":"6598977.0000","HeartEX2wt_199":"4329215.0000","HeartEX2wt_51":"5643770.0000","HeartEX2wt_93":"2430146.0000","WTFemale_200":"304109.7000","WTFemale_220":"376898.6000","WTFemale_221":"300146.1000","WTMale_204":"164518.5000","WTMale_207":"184754.3000","WTMale_218":"423382.0000"},{"Metabolite":"4-Hydroxyproline","KOFemale_1030":"583894.3000","KOFemale_1059":"685401.5000","KOFemale_1061":"728246.1000","KOMale_1040":"639082.8000","KOMale_1042":"722296.4000","KOMale_1069":"856587.6000","MUTFemale_340":"3158005.0000","MUTFemale_358":"878508.4000","MUTFemale_390":"707596.1000","MUTMale_226":"959046.3000","MUTMale_356":"1383580.0000","MUTMale_433":"851983.5000","HeartY8PTgE_50":"1030225.0000","HeartY8PTgE_94":"1315677.0000","HeartY8PTgE_96":"1786146.0000","HeartY8PTgE_99":"1116990.0000","HeartEX2wt_184":"1644938.0000","HeartEX2wt_199":"1306916.0000","HeartEX2wt_51":"1598396.0000","HeartEX2wt_93":"1235957.0000","WTFemale_200":"1034122.0000","WTFemale_220":"819961.5000","WTFemale_221":"744732.2000","WTMale_204":"1096486.0000","WTMale_207":"754468.3000","WTMale_218":"585808.1000"},{"Metabolite":"4-Trimethylammoniobutanoic 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