Journal article
Tubular Mitochondrial Pyruvate Carrier Disruption Elicits Redox Adaptations that Protect from Acute Kidney Injury
Molecular metabolism (Germany), Vol.79, 101849
01/2024
DOI: 10.1016/j.molmet.2023.101849
PMCID: PMC10733108
PMID: 38056691
Abstract
OBJECTIVE Energy-intensive kidney reabsorption processes essential for normal whole-body function are maintained by tubular epithelial cell metabolism. Although tubular metabolism changes markedly following acute kidney injury (AKI), it remains unclear which metabolic alterations are beneficial or detrimental. By analyzing large-scale, publicly available datasets, we observed that AKI consistently leads to downregulation of the mitochondrial pyruvate carrier (MPC). This investigation aimed to understand the contribution of the tubular MPC to kidney function, metabolism, and acute injury severity. METHODS We generated tubular epithelial cell-specific Mpc1 knockout (MPC TubKO) mice and employed renal function tests, in vivo renal 13C-glucose tracing, mechanistic enzyme activity assays, and tests of injury and survival in an established rhabdomyolysis model of AKI.RESULTSMPC TubKO mice retained normal kidney function, displayed unchanged markers of kidney injury, but exhibited coordinately increased enzyme activities of the pentose phosphate pathway and the glutathione and thioredoxin oxidant defense systems. Following rhabdomyolysis-induced AKI, compared to WT control mice, MPC TubKO mice showed increased glycolysis, decreased kidney injury and oxidative stress markers, and strikingly increased survival. CONCLUSIONS Our findings suggest that decreased renal tubular mitochondrial pyruvate uptake hormetically upregulates oxidant defense systems before AKI and is a beneficial adaptive response after rhabdomyolysis-induced AKI. This raises the possibility of therapeutically modulating the MPC to attenuate AKI severity.
Details
- Title: Subtitle
- Tubular Mitochondrial Pyruvate Carrier Disruption Elicits Redox Adaptations that Protect from Acute Kidney Injury
- Creators
- Adam J Rauckhorst - University of IowaGabriela Vasquez Martinez - Nationwide Children's HospitalGabriel Mayoral Andrade - Nationwide Children's HospitalHsiang Wen - University of IowaJi Young Kim - The Ohio State UniversityAaron Simoni - Nationwide Children's HospitalClaudia Robles-Planells - Nationwide Children's HospitalKranti A Mapuskar - University of IowaPrerna Rastogi - University of IowaEmily J Steinbach - University of IowaMichael L McCormick - University of IowaBryan G Allen - University of IowaNavjot S PablaAshley R Jackson - Nationwide Children's HospitalMitchell C Coleman - University of IowaDouglas R Spitz - University of IowaEric B Taylor - University of IowaDiana Zepeda-Orozco
- Resource Type
- Journal article
- Publication Details
- Molecular metabolism (Germany), Vol.79, 101849
- DOI
- 10.1016/j.molmet.2023.101849
- PMID
- 38056691
- PMCID
- PMC10733108
- NLM abbreviation
- Mol Metab
- eISSN
- 2212-8778
- Grant note
- DOI: 10.13039/100000041, name: American Diabetes Association; DOI: 10.13039/100000054, name: National Cancer Institute; DOI: 10.13039/100000062, name: National Institute of Diabetes and Digestive and Kidney Diseases; DOI: 10.13039/100000069, name: National Institute of Arthritis and Musculoskeletal and Skin Diseases; DOI: 10.13039/100000968, name: American Heart Association Inc; DOI: 10.13039/100009633, name: Eunice Kennedy Shriver National Institute of Child Health and Human Development
- Language
- English
- Electronic publication date
- 12/04/2023
- Date published
- 01/2024
- Academic Unit
- Molecular Physiology and Biophysics; Nephrology, Dialysis and Transplantation; Stead Family Department of Pediatrics; Pathology; Orthopedics and Rehabilitation; Biology; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center
- Record Identifier
- 9984520559002771
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