Summary of Study ST002403

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.

See: https://www.metabolomicsworkbench.org/about/howtocite.php

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.

Study ID	ST002403
Study Title	Deep multi-omic profiling reveals extensive mitochondrial remodeling driven by glycemia in early diabetic kidney disease (Mitochondria)
Study Summary	Changes 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 transporter 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	Baker Heart and Diabetes Institute
Laboratory	Metabolomics
Last Name	Huynh
First Name	Kevin
Address	75 Commercial Road, Melbourne, 3004
Email	kevin.huynh@baker.edu.au
Phone	0385321537
Submit Date	2022-11-20
Num Groups	3
Raw Data Available	Yes
Raw Data File Type(s)	mzML
Analysis Type Detail	LC-MS
Release Date	2023-12-01
Release Version	1

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Sample Preparation:

Sampleprep ID:	SP002498
Sampleprep Summary:	Lipidomic analysis. Lipids were extracted from mitochondrial isolates using a single-phase chloroform/methanol extraction as described previously (87). Briefly, 20 volumes of chloroform:methanol (2:1) were added to the sample along with a series of internal standards. Samples were vortexed and centrifuged on a rotary mixer for 10 min. Following 30 min of sonication on a sonicator bath, samples were rested for 20 min before being centrifuged at 13,000 g for 10 min. Supernatants were transferred into a 96 well plate, dried down, and reconstituted in 50 µL H2O saturated butanol, before being sonicated for 10 min. Following the addition of 50 µL of methanol with 10 mM ammonium formate, samples were centrifuged at 4000 rpm on a plate centrifuge and transferred into glass vials with inserts for mass spectrometry analysis.

Sampleprep ID:

SP002498

Sampleprep Summary:

Lipidomic analysis. Lipids were extracted from mitochondrial isolates using a single-phase chloroform/methanol extraction as described previously (87). Briefly, 20 volumes of chloroform:methanol (2:1) were added to the sample along with a series of internal standards. Samples were vortexed and centrifuged on a rotary mixer for 10 min. Following 30 min of sonication on a sonicator bath, samples were rested for 20 min before being centrifuged at 13,000 g for 10 min. Supernatants were transferred into a 96 well plate, dried down, and reconstituted in 50 µL H2O saturated butanol, before being sonicated for 10 min. Following the addition of 50 µL of methanol with 10 mM ammonium formate, samples were centrifuged at 4000 rpm on a plate centrifuge and transferred into glass vials with inserts for mass spectrometry analysis.