Targeting methylglyoxal in diabetic kidney disease using the mitochondria-targeted compound MitoGamide

Tan, S. M. et al. (2021) Targeting methylglyoxal in diabetic kidney disease using the mitochondria-targeted compound MitoGamide. Nutrients, 13(5), 1457. (doi: 10.3390/nu13051457) (PMID:33922959) (PMCID:PMC8145135)

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Diabetic kidney disease (DKD) remains the number one cause of end-stage renal disease in the western world. In experimental diabetes, mitochondrial dysfunction in the kidney precedes the development of DKD. Reactive 1,2-dicarbonyl compounds, such as methylglyoxal, are generated from sugars both endogenously during diabetes and exogenously during food processing. Methylglyoxal is thought to impair the mitochondrial function and may contribute to the pathogenesis of DKD. Here, we sought to target methylglyoxal within the mitochondria using MitoGamide, a mitochondria-targeted dicarbonyl scavenger, in an experimental model of diabetes. Male 6-week-old heterozygous Akita mice (C57BL/6-Ins2-Akita/J) or wildtype littermates were randomized to receive MitoGamide (10 mg/kg/day) or a vehicle by oral gavage for 16 weeks. MitoGamide did not alter the blood glucose control or body composition. Akita mice exhibited hallmarks of DKD including albuminuria, hyperfiltration, glomerulosclerosis, and renal fibrosis, however, after 16 weeks of treatment, MitoGamide did not substantially improve the renal phenotype. Complex-I-linked mitochondrial respiration was increased in the kidney of Akita mice which was unaffected by MitoGamide. Exploratory studies using transcriptomics identified that MitoGamide induced changes to olfactory signaling, immune system, respiratory electron transport, and post-translational protein modification pathways. These findings indicate that targeting methylglyoxal within the mitochondria using MitoGamide is not a valid therapeutic approach for DKD and that other mitochondrial targets or processes upstream should be the focus of therapy.

Item Type:Articles
Additional Information:Funding: This work was supported by a project grant from the National Health and Medical Research Council of Australia (NHMRC, GNT1101309) and a JDRF/NHMRC Centre of Research Excellence grant (GNT1078609). This work was also supported in part by the Victorian Government’s Operational Infrastructure Support Program. M.T.C. is the recipient of a Career Development Award from JDRF Australia, the recipient of the Australian Research Council Special Research Initiative in Type 1 Juvenile Diabetes. S.M.T. is supported by a JDRF Advanced Postdoctoral Fellowship. M.E.C. is supported by a NHMRC Level 3 Investigator Grant (GNT1175760). Work in the Murphy lab is supported by the Medical Research Council UK (MC_U105663142) and by a Wellcome Trust Investigator award (110159/Z/15/Z); work in the Hartley lab was supported by the Biotechnology and Biological Sciences Research Council Grant (BB/I012826/1), Wellcome Trust Investigator award (110158/Z/15/Z), and a Consejo Nacional de Ciencia y Technología studentship (to C.D.B.-G.).
Glasgow Author(s) Enlighten ID:Caldwell, Dr Stuart and Hartley, Professor Richard
Creator Roles:
Caldwell, S.Resources
Hartley, R.Resources
Authors: Tan, S. M., Lindblom, R. S. J., Ziemann, M., Laskowski, A., Granata, C., Snelson, M., Thallas-Bonke, V., El-Osta, A., Baeza-Garza, C. D., Caldwell, S. T., Hartley, R. C., Krieg, T., Cooper, M. E., Murphy, M. P., and Coughlan, M. T.
College/School:College of Science and Engineering > School of Chemistry
Journal Name:Nutrients
ISSN (Online):2072-6643
Published Online:25 April 2021
Copyright Holders:Copyright © 2021 by the authors
First Published:First published in Nutrients 13(5):1457
Publisher Policy:Reproduced under a Creative Commons Licence

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
165401Developing chemical mass spectrometry probes to assess the production of reactive oxygen species in vivoRichard HartleyBiotechnology and Biological Sciences Research Council (BBSRC)BB/I012826/1Chemistry
172617Exploring mitochondrial metabolism in health and disease using targeted biological chemistryRichard HartleyWellcome Trust (WELLCOTR)110158/Z/15/ZChemistry