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L-carnitine co-administration prevents colistin-induced mitochondrial permeability transition and reduces the risk of acute kidney injury in mice.
- Source :
-
Scientific reports [Sci Rep] 2024 Jul 16; Vol. 14 (1), pp. 16444. Date of Electronic Publication: 2024 Jul 16. - Publication Year :
- 2024
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Abstract
- Colistin is a polymyxin antibiotic currently experiencing renewed clinical interest due to its efficacy in the treatment of multidrug resistant (MDR) bacterial infections. The frequent onset of acute dose-dependent kidney injury, with the potential of leading to long-term renal damage, has limited its use and hampered adequate dosing regimens, increasing the risk of suboptimal plasma concentrations during treatment. The mechanism of colistin-induced renal toxicity has been postulated to stem from mitochondrial damage, yet there is no direct evidence of colistin acting as a mitochondrial toxin. The aim of this study was to evaluate whether colistin can directly induce mitochondrial toxicity and, if so, uncover the underlying molecular mechanism. We found that colistin leads to a rapid permeability transition of mitochondria isolated from mouse kidney that was fully prevented by co-incubation of the mitochondria with desensitizers of the mitochondrial transition pore cyclosporin A or L-carnitine. The protective effect of L-carnitine was confirmed in experiments in primary cultured mouse tubular cells. Consistently, the relative risk of colistin-induced kidney damage, calculated based on histological analysis as well as by the early marker of tubular kidney injury, Kim-1, was halved under co-administration with L-carnitine in vivo. Notably, L-carnitine neither affected the pharmacokinetics of colistin nor its antimicrobial activity against relevant bacterial strains. In conclusion, colistin targets the mitochondria and induces permeability transition thereof. L-carnitine prevents colistin-induced permeability transition in vitro. Moreover, L-carnitine co-administration confers partial nephroprotection in mice treated with colistin, without interfering with its pharmacokinetics and antibacterial activity.<br /> (© 2024. The Author(s).)
- Subjects :
- Animals
Mice
Male
Mitochondrial Permeability Transition Pore metabolism
Kidney drug effects
Kidney metabolism
Kidney pathology
Mice, Inbred C57BL
Cyclosporine
Colistin adverse effects
Colistin administration & dosage
Acute Kidney Injury prevention & control
Acute Kidney Injury chemically induced
Acute Kidney Injury metabolism
Carnitine pharmacology
Carnitine administration & dosage
Mitochondria drug effects
Mitochondria metabolism
Anti-Bacterial Agents pharmacology
Anti-Bacterial Agents administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 14
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 39013979
- Full Text :
- https://doi.org/10.1038/s41598-024-67171-x