ALKBH7 mediates necrosis via rewiring of glyoxal metabolism
- Univeristy of Rochester Medical Center, United States
- University of Rochester Medical Center, United States
- National Institutes of Health, United States
- University of Rochester, United States
Abstract
Alkb homolog 7 (ALKBH7) is a mitochondrial α-ketoglutarate dioxygenase required for DNA alkylation induced necrosis, but its function and substrates remain unclear. Herein we show ALKBH7 regulates dialdehyde metabolism, which impacts the cardiac response to ischemia-reperfusion (IR) injury. Using a multi-omics approach, we find no evidence ALKBH7 functions as a prolyl-hydroxylase, but we do find Alkbh7-/- mice have elevated glyoxalase I (GLO-1), a dialdehyde detoxifying enzyme. Metabolic pathways related to the glycolytic by-product methylglyoxal (MGO) are rewired in Alkbh7-/- mice, along with elevated levels of MGO protein adducts. Despite greater glycative stress, hearts from Alkbh7-/- mice are protected against IR injury, in a manner blocked by GLO-1 inhibition. Integrating these observations, we propose ALKBH7 regulates glyoxal metabolism, and that protection against necrosis and cardiac IR injury bought on by ALKBH7 deficiency originates from the signaling response to elevated MGO stress.
Data availability
The complete original data set used to generate all figures is attached as a Microsoft Excel file, with the submitted files. A DOI has been reserved at the data sharing site FigShare (DOI: 10.6084/m9.figshare.12200273) and the file has been uploaded there.
Article and author information
Author details
Chaitanya A Kulkarni
Funding
National Institutes of Health (R01-HL071158)
- Paul S Brookes
American Heart Association (#19POST34380212)
- Chaitanya A Kulkarni
NIH Office of the Director (ZO1-HL002066)
- Leslie Kennedy
- Elizabeth Murphy
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Arduino A Mangoni, Flinders Medical Centre, Australia
Ethics
Animal experimentation: All animal work was conducted according to the "NIH Guide" (8th edition, 2011). Animals were housed in an AAALAC accredited facility with food and water available ad libitum. All procedures were performed under tribromoethanol anesthesia. All animal work was approved by the University of Rochester Committee on Animal Resources (UCAR protocol # 2007-087).
Version history
- Received: May 5, 2020
- Accepted: August 13, 2020
- Accepted Manuscript published: August 14, 2020 (version 1)
- Version of Record published: August 21, 2020 (version 2)
Copyright
© 2020, Kulkarni et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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ALKBH7 mediates necrosis via rewiring of glyoxal metabolism
eLife 9:e58573.
https://doi.org/10.7554/eLife.58573
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