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MetaboLights MTBLS173 - GNPS Comprehensive Metabolic Profiling of Age-Related Mitochondrial Dysfunction in the High-Fat-Fed ob/ob Mouse Heart

ABSTRACT: This data set was downloaded from MetaboLights (http://www.ebi.ac.uk/metabolights/) accession number MTBLS173 Abstract:The ectopic deposition of fat is thought to lead to lipotoxicity and has been associated with mitochondrial dysfunction and diabetic cardiomyopathy. We have measured mitochondrial respiratory capacities in the hearts of ob/ob and wild-type mice on either a regular chow (RCD) or high-fat (HFD) diet across four age groups to investigate the impact of diet and age on mitochondrial function alongside a comprehensive strategy for metabolic profiling of the tissue. Myocardial mitochondrial dysfunction was only evident in ob/ob mice on RCD at 14 months, but it was detectable at 3 months on the HFD. Liquid chromatography–mass spectrometry (LC–MS) was used to study the profiles of acylcarnitines and the accumulation of triglycerides, but neither class of lipid was associated with mitochondrial dysfunction. However, a targeted LC–MS/MS analysis of markers of oxidative stress demonstrated increases in GSSG/GSH and 8-oxoguanine, in addition to the accumulation of diacylglycerols, which are lipid species linked to lipotoxicity. Our results demonstrate that myocardial mitochondria in ob/ob mice on RCD maintained a similar respiratory capacity to that of wild type until a late stage in aging. However, on a HFD, unlike wild-type mice, ob/ob mice failed to increase mitochondrial respiration, which may be associated with a complex I defect following increased oxidative damage.

INSTRUMENT(S): API 5500 QTRAP (AB Sciex)

ORGANISM(S): Mus Musculus

SUBMITTER: Wang

PROVIDER: MSV000082758 | GNPS | Tue Aug 07 09:35:00 BST 2018

REPOSITORIES: GNPS

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Project description:Background. Many age-associated disorders (including diabetes, cancer, and neurodegenerative diseases) have been linked to mitochondrial dysfunction, which leads to impaired cellular bioenegetics (decreased ATP production) and increased oxidative stress. However, it is not known what genetic and molecular pathways underlie differential vulnerability to mitochondrial dysfunction observed among different cell types. Methodology/Principal Findings. Starting with CRI-G1 insulinoma cells as a model of a neuronal/endocrine cell type, we isolated a novel (CRI-G1-RS) cell line that was more susceptible to cell death induced by mitochondrial respiratory chain inhibitors or direct oxidants than the parental CRI-G1 cell line (for clarity renamed CRI-G1-RR). In contrast, RS cells were equally vulnerable to mitochondrial uncoupling and less vulnerable to protein kinase inhibition than RR cells, suggesting that differences in vulnerability to mitochondrial toxins among the two cell types did not stem from differences in ATP production/utilization or in downstream apoptotic machinery. Genome-wide gene expression analysis and follow-up biochemical studies revealed that, in this experimental system, increased vulnerability to mitochondrial and oxidative stress was associated with (1) inhibition of ARE/Nrf2/Keap1 antioxidant pathway; (2) decreased expression of antioxidant and phase I/II conjugation enzymes, most of which are Nrf2 transcriptional targets; (3) increased expression of molecular chaperones, many of which are also considered Nrf2 transcriptional targets; and (4) increased expression of β cell-specific genes and transcription factors that specify/maintain β cell fate. Conclusions/Significance. The molecular profile presented here will enable identification of individual genes and/or gene clusters that shape vulnerability to mitochondrial dysfunction and thus represent potential therapeutic targets for diabetes and neurodegenerative diseases. In addition, the newly identified CRI-G1-RS cell line represents a new experimental model for investigating how endogenous antioxidants affect glucose sensing and insulin release by pancreatic β cells. Six biological replicates for each of two cell types (12 samples total)

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MetaboLights MTBLS173 - GNPS Comprehensive Metabolic Profiling of Age-Related Mitochondrial Dysfunction in the High-Fat-Fed ob/ob Mouse Heart

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