Summary of Study ST002382

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 PR001532. The data can be accessed directly via it's Project DOI: 10.21228/M8P11T 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 IDST002382
Study TitleDeep multi-omic profiling reveals extensive mitochondrial remodeling driven by glycemia in early diabetic kidney disease
Study SummaryChanges in mitochondrial energy metabolism are thought to be central to the development of diabetic kidney disease (DKD); however, whether this response is explicitly driven by systemic glucose concentrations remains unknown. Here, we show that titrating blood glucose concentrations in vivo directly impacts mitochondrial morphology and bioenergetics and remodels the mitochondrial proteome in the kidney in early DKD. Mitoproteomic analysis revealed profound metabolic disturbances induced by severe hyperglycemia, including upregulation of enzymes involved in the TCA cycle and fatty acid metabolism, enhanced ketogenesis as well as extensive dysregulation of the mitochondrial SLC25 carrier family. The metabolite and lipid landscape were perturbed by severe hyperglycemia; untargeted metabolomics and lipidomics confirmed the enrichment of TCA cycle metabolites, an increase in triglyceride concentrations, and extensive and specific cardiolipin remodeling. Lowering blood glucose to moderate hyperglycemia stabilized all three omic landscapes, partially prevented changes in mitochondrial morphology and bioenergetics, and improved kidney injury. This study provides insights into altered substrate utilization and energy generation in the kidney early in diabetes, during moderate and severe hyperglycemia and has implications for therapeutic strategies aiming at the reinvigoration of mitochondrial function and signaling in diabetes.
Institute
University of Melbourne
Last NameCaruana
First NameNikeisha
Address30 Flemington Rd, Parkville VIC 3052
Emailnikeisha.caruana@unimelb.edu.au
Phone0383442219
Submit Date2022-11-09
Raw Data AvailableYes
Raw Data File Type(s)mzXML
Analysis Type DetailLC-MS
Release Date2022-12-27
Release Version1
Nikeisha Caruana Nikeisha Caruana
https://dx.doi.org/10.21228/M8P11T
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Collection:

Collection ID:CO002464
Collection Summary:Metabolite extraction was carried out as previously described (96). Briefly, ~20-30 mg of kidney cortex was homogenized under cryogenic conditions in cryomill tubes containing beads for homogenization (Precellys bead-mill with a Cryolys attachment, Bertin Technologies, France) and 600 mL of 3:1 methanol:water (v/v) containing 0.5 nmol 13C6-sorbitol and 5 nmol 13C5,15N-valine as internal standards. Homogenates (480 mL) were subsequently vortexed in fresh Eppendorf tubes containing 120 ml chloroform. The resultant extracts were centrifuged to pellet cell debris and precipitated protein. The supernatant was used for subsequent analysis. In addition, an aliquot from each sample was pooled and re-aliquoted to generate pooled biological quality controls (PBQC). Samples and PBQCs were evaporated dry by speed vacuum centrifugation and then derivatized online using the Shimadzu AOC6000 autosampler robot with methoxyamine hydrochloride (30 mg/mL in pyridine) and N, O - bis (trimethylsilyl) trifluoroacetamide [BSTFA] + 1% chlorotrimethylsilane [TMCS] (both Thermo Fisher Scientific, Waltham, USA). Samples were left for 1 h before 1 µL was injected onto the GC column using a hot needle technique. Split (1:10) injections were performed for each sample.
Sample Type:Kidney
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