{
"METABOLOMICS WORKBENCH":{"STUDY_ID":"ST002068","ANALYSIS_ID":"AN003371","VERSION":"1","CREATED_ON":"January 28, 2022, 3:19 pm"},

"PROJECT":{"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"},

"STUDY":{"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","EMAIL":"nns4001@med.cornell.edu","PHONE":"646-962-8172"},

"SUBJECT":{"SUBJECT_TYPE":"Mammal","SUBJECT_SPECIES":"Mus musculus","TAXONOMY_ID":"10090"},
"SUBJECT_SAMPLE_FACTORS":[
{
"Subject ID":"-",
"Sample ID":"S75dCtrl_1",
"Factors":{"Genotype":"WT","Sex":"M","Age (d)":"75"},
"Additional sample data":{"RAW_FILE_NAME":"75dCtrl_1.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"S75dCtrl_2",
"Factors":{"Genotype":"WT","Sex":"F","Age (d)":"75"},
"Additional sample data":{"RAW_FILE_NAME":"75dCtrl_2.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"S75dCtrl_3",
"Factors":{"Genotype":"WT","Sex":"F","Age (d)":"75"},
"Additional sample data":{"RAW_FILE_NAME":"75dCtrl_3.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"S75dCtrl_4",
"Factors":{"Genotype":"WT","Sex":"M","Age (d)":"75"},
"Additional sample data":{"RAW_FILE_NAME":"75dCtrl_4.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"S75dCtrl_5",
"Factors":{"Genotype":"WT","Sex":"M","Age (d)":"75"},
"Additional sample data":{"RAW_FILE_NAME":"75dCtrl_5.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"S75dMut_1",
"Factors":{"Genotype":"CHCHD10 S55L+/-","Sex":"F","Age (d)":"75"},
"Additional sample data":{"RAW_FILE_NAME":"75dMut_1.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"S75dMut_2",
"Factors":{"Genotype":"CHCHD10 S55L+/-","Sex":"F","Age (d)":"75"},
"Additional sample data":{"RAW_FILE_NAME":"75dMut_2.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"S75dMut_3",
"Factors":{"Genotype":"CHCHD10 S55L+/-","Sex":"M","Age (d)":"75"},
"Additional sample data":{"RAW_FILE_NAME":"75dMut_3.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"S75dMut_4",
"Factors":{"Genotype":"CHCHD10 S55L+/-","Sex":"M","Age (d)":"75"},
"Additional sample data":{"RAW_FILE_NAME":"75dMut_4.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"S75dMut_5",
"Factors":{"Genotype":"CHCHD10 S55L+/-","Sex":"M","Age (d)":"75"},
"Additional sample data":{"RAW_FILE_NAME":"75dMut_5.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"S125dCtrl_6",
"Factors":{"Genotype":"WT","Sex":"F","Age (d)":"125"},
"Additional sample data":{"RAW_FILE_NAME":"125dCtrl_6.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"S125dCtrl_7",
"Factors":{"Genotype":"WT","Sex":"M","Age (d)":"125"},
"Additional sample data":{"RAW_FILE_NAME":"125dCtrl_7.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"S125dCtrl_8",
"Factors":{"Genotype":"WT","Sex":"F","Age (d)":"125"},
"Additional sample data":{"RAW_FILE_NAME":"125dCtrl_8.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"S125dCtrl_9",
"Factors":{"Genotype":"WT","Sex":"M","Age (d)":"125"},
"Additional sample data":{"RAW_FILE_NAME":"125dCtrl_9.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"S125dCtrl_10",
"Factors":{"Genotype":"WT","Sex":"M","Age (d)":"125"},
"Additional sample data":{"RAW_FILE_NAME":"125dCtrl_10.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"S125dCtrl_11",
"Factors":{"Genotype":"WT","Sex":"M","Age (d)":"125"},
"Additional sample data":{"RAW_FILE_NAME":"125dCtrl_11.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"S125dMut_6",
"Factors":{"Genotype":"CHCHD10 S55L+/-","Sex":"F","Age (d)":"125"},
"Additional sample data":{"RAW_FILE_NAME":"125dMut_6.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"S125dMut_7",
"Factors":{"Genotype":"CHCHD10 S55L+/-","Sex":"F","Age (d)":"125"},
"Additional sample data":{"RAW_FILE_NAME":"125dMut_7.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"S125dMut_8",
"Factors":{"Genotype":"CHCHD10 S55L+/-","Sex":"M","Age (d)":"125"},
"Additional sample data":{"RAW_FILE_NAME":"125dMut_8.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"S125dMut_9",
"Factors":{"Genotype":"CHCHD10 S55L+/-","Sex":"F","Age (d)":"125"},
"Additional sample data":{"RAW_FILE_NAME":"125dMut_9.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"S125dMut_10",
"Factors":{"Genotype":"CHCHD10 S55L+/-","Sex":"F","Age (d)":"125"},
"Additional sample data":{"RAW_FILE_NAME":"125dMut_10.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"S125dMut_11",
"Factors":{"Genotype":"CHCHD10 S55L+/-","Sex":"M","Age (d)":"125"},
"Additional sample data":{"RAW_FILE_NAME":"125dMut_11.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"S225dCtrl_12",
"Factors":{"Genotype":"WT","Sex":"F","Age (d)":"225"},
"Additional sample data":{"RAW_FILE_NAME":"225dCtrl_12.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"S225dCtrl_13",
"Factors":{"Genotype":"WT","Sex":"F","Age (d)":"225"},
"Additional sample data":{"RAW_FILE_NAME":"225dCtrl_13.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"S225dCtrl_14",
"Factors":{"Genotype":"WT","Sex":"M","Age (d)":"225"},
"Additional sample data":{"RAW_FILE_NAME":"225dCtrl_14.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"S225dCtrl_15",
"Factors":{"Genotype":"WT","Sex":"M","Age (d)":"225"},
"Additional sample data":{"RAW_FILE_NAME":"225dCtrl_15.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"S225dCtrl_16",
"Factors":{"Genotype":"WT","Sex":"M","Age (d)":"225"},
"Additional sample data":{"RAW_FILE_NAME":"225dCtrl_16.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"S225dMut_12",
"Factors":{"Genotype":"CHCHD10 S55L+/-","Sex":"M","Age (d)":"225"},
"Additional sample data":{"RAW_FILE_NAME":"225dMut_12.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"S225dMut_13",
"Factors":{"Genotype":"CHCHD10 S55L+/-","Sex":"F","Age (d)":"225"},
"Additional sample data":{"RAW_FILE_NAME":"225dMut_13.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"S225dMut_14",
"Factors":{"Genotype":"CHCHD10 S55L+/-","Sex":"M","Age (d)":"225"},
"Additional sample data":{"RAW_FILE_NAME":"225dMut_14.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"S225dMut_15",
"Factors":{"Genotype":"CHCHD10 S55L+/-","Sex":"M","Age (d)":"225"},
"Additional sample data":{"RAW_FILE_NAME":"225dMut_15.mzXML"}
},
{
"Subject ID":"-",
"Sample ID":"S225dMut_16",
"Factors":{"Genotype":"CHCHD10 S55L+/-","Sex":"F","Age (d)":"225"},
"Additional sample data":{"RAW_FILE_NAME":"225dMut_16.mzXML"}
}
],
"COLLECTION":{"COLLECTION_SUMMARY":"Murine heart tissue was excised and snap frozen in liquid N2.","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":{"CHROMATOGRAPHY_TYPE":"HILIC","INSTRUMENT_NAME":"Thermo Vanquish","COLUMN_NAME":"SeQuant ZIC- pHILIC (150 x 2.1mm, 5um)"},

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

"MS":{"INSTRUMENT_NAME":"Thermo Q Exactive Orbitrap","INSTRUMENT_TYPE":"Orbitrap","MS_TYPE":"ESI","ION_MODE":"NEGATIVE","MS_COMMENTS":"-"},

"MS_METABOLITE_DATA":{
"Units":"Peak Intensity",

"Data":[{"Metabolite":"D-Glucose","S125dCtrl_10":"4865061","S125dCtrl_11":"2042894","S125dCtrl_6":"4096494","S125dCtrl_7":"2043236","S125dCtrl_8":"7834317","S125dCtrl_9":"2408456","S125dMut_10":"3860415","S125dMut_11":"1195007","S125dMut_6":"4571502","S125dMut_7":"8291768","S125dMut_8":"2937373","S125dMut_9":"4246668","S225dCtrl_12":"5244229","S225dCtrl_13":"3480874","S225dCtrl_14":"8684254","S225dCtrl_15":"9754421","S225dCtrl_16":"7897856","S225dMut_12":"1650818","S225dMut_13":"1655073","S225dMut_14":"1314514","S225dMut_15":"17594030","S225dMut_16":"7170946","S75dCtrl_1":"1546459","S75dCtrl_2":"1620009","S75dCtrl_3":"1960781","S75dCtrl_4":"4063461","S75dCtrl_5":"3306034","S75dMut_1":"2577742","S75dMut_2":"1753479","S75dMut_3":"1658118","S75dMut_4":"1767687","S75dMut_5":"1938970"},{"Metabolite":"Myoinositol","S125dCtrl_10":"11203540","S125dCtrl_11":"2801385","S125dCtrl_6":"3849758","S125dCtrl_7":"4298243","S125dCtrl_8":"3381177","S125dCtrl_9":"2988894","S125dMut_10":"4342773","S125dMut_11":"5107156","S125dMut_6":"5149885","S125dMut_7":"14738650","S125dMut_8":"7368278","S125dMut_9":"6053654","S225dCtrl_12":"15236220","S225dCtrl_13":"6394965","S225dCtrl_14":"4166778","S225dCtrl_15":"5438236","S225dCtrl_16":"11655530","S225dMut_12":"7448058","S225dMut_13":"7292486","S225dMut_14":"7128891","S225dMut_15":"10298740","S225dMut_16":"11577140","S75dCtrl_1":"1549197","S75dCtrl_2":"2869198","S75dCtrl_3":"3563225","S75dCtrl_4":"3927945","S75dCtrl_5":"2411717","S75dMut_1":"6216615","S75dMut_2":"3996265","S75dMut_3":"6047882","S75dMut_4":"5329106","S75dMut_5":"3121092"},{"Metabolite":"Cyclic AMP","S125dCtrl_10":"0","S125dCtrl_11":"25889.21","S125dCtrl_6":"0","S125dCtrl_7":"9980.371","S125dCtrl_8":"57404.77","S125dCtrl_9":"13177.03","S125dMut_10":"0","S125dMut_11":"0","S125dMut_6":"15490","S125dMut_7":"18354.53","S125dMut_8":"8608.538","S125dMut_9":"0","S225dCtrl_12":"19600.45","S225dCtrl_13":"0","S225dCtrl_14":"0","S225dCtrl_15":"13653.1","S225dCtrl_16":"0","S225dMut_12":"0","S225dMut_13":"0","S225dMut_14":"0","S225dMut_15":"0","S225dMut_16":"13610.49","S75dCtrl_1":"28125.83","S75dCtrl_2":"35264.23","S75dCtrl_3":"42775.94","S75dCtrl_4":"541276.6","S75dCtrl_5":"75432.55","S75dMut_1":"169405.6","S75dMut_2":"198649.6","S75dMut_3":"0","S75dMut_4":"23984.28","S75dMut_5":"96684.59"},{"Metabolite":"Thiamine","S125dCtrl_10":"4763023","S125dCtrl_11":"1961573","S125dCtrl_6":"5631280","S125dCtrl_7":"5634242","S125dCtrl_8":"8165995","S125dCtrl_9":"1837912","S125dMut_10":"8482564","S125dMut_11":"3469358","S125dMut_6":"8278699","S125dMut_7":"4161858","S125dMut_8":"5227805","S125dMut_9":"11826510","S225dCtrl_12":"1373710","S225dCtrl_13":"4042074","S225dCtrl_14":"2521650","S225dCtrl_15":"3138167","S225dCtrl_16":"2394270","S225dMut_12":"4411451","S225dMut_13":"7445160","S225dMut_14":"3637800","S225dMut_15":"7816517","S225dMut_16":"2312774","S75dCtrl_1":"196900.1","S75dCtrl_2":"250414.5","S75dCtrl_3":"169767.8","S75dCtrl_4":"6073274","S75dCtrl_5":"5615406","S75dMut_1":"374494.7","S75dMut_2":"379314.7","S75dMut_3":"6355271","S75dMut_4":"7262660","S75dMut_5":"978008"},{"Metabolite":"Thiamine monophosphate","S125dCtrl_10":"75237.73","S125dCtrl_11":"196221.9","S125dCtrl_6":"102842","S125dCtrl_7":"154112.9","S125dCtrl_8":"202701.8","S125dCtrl_9":"61807.34","S125dMut_10":"0","S125dMut_11":"83587.44","S125dMut_6":"68413.63","S125dMut_7":"136604.2","S125dMut_8":"56021.14","S125dMut_9":"0","S225dCtrl_12":"234060.3","S225dCtrl_13":"423047.4","S225dCtrl_14":"105519.5","S225dCtrl_15":"217294.8","S225dCtrl_16":"116573.7","S225dMut_12":"131137.5","S225dMut_13":"212780.3","S225dMut_14":"141383.3","S225dMut_15":"0","S225dMut_16":"52226.48","S75dCtrl_1":"108546.7","S75dCtrl_2":"130180","S75dCtrl_3":"137683.6","S75dCtrl_4":"225074.3","S75dCtrl_5":"167427.9","S75dMut_1":"70346.95","S75dMut_2":"151006.5","S75dMut_3":"47199.72","S75dMut_4":"139015.4","S75dMut_5":"87867.57"},{"Metabolite":"Guanosine 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acid","HMDB":"HMDB00254"},{"Metabolite":"CDP","HMDB":"HMDB01546"},{"Metabolite":"N-Acetylornithine","HMDB":"HMDB03357"}]
}

}