Lasmiditan restores mitochondrial quality control mechanisms and accelerates renal recovery after ischemia-reperfusion injury.

Autor: Hurtado KA; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, USA., Janda J; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, USA., Schnellmann RG; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, USA; Southern Arizona VA Health Care System, Tucson, AZ, USA; Southwest Environmental Health Science Center, University of Arizona, Tucson, AZ, USA. Electronic address: schnell@arizona.edu.
Jazyk: angličtina
Zdroj: Biochemical pharmacology [Biochem Pharmacol] 2023 Dec; Vol. 218, pp. 115855. Date of Electronic Publication: 2023 Oct 21.
DOI: 10.1016/j.bcp.2023.115855
Abstrakt: Background: Mitochondrial dysfunction is a well-established result of acute kidney injury (AKI). Previously, we identified that 5-hydroxytryptamine 1F (5-HT 1F ) receptor agonism with lasmiditan induces mitochondrial biogenesis (MB) and improves renal vasculature and function in an AKI mouse model. We hypothesize that lasmiditan also modulates mitochondrial dynamics and mitophagy in a mouse model of AKI.
Methods: Male mice were subjected to renal ischemia/reperfusion (I/R) and treated daily with lasmiditan (0.3 mg/kg) or vehicle beginning 24 h after injury for 3 or 6d. Serum creatinine was measured to estimate glomerular filtration. Electron microscopy was used to assess mitochondrial morphology and mitophagy. Mitochondrial-related protein were confirmed with immunoblotting. Mitochondrial function was assessed with ATP measurements.
Results: Lasmiditan treatment improved mitochondrial and kidney recovery as early as 3d post-AKI, as evidenced by increased ATP, and decreased serum creatinine, respectively. Electron micrographs of renal cortices revealed that lasmiditan also decreased mitochondrial damage and increased mitochondrial area and size by 6d after I/R injury. Additionally, lasmiditan treatment increased mitolysosomes by 3d, indicating induction of mitophagy. Phosphorylation of mitophagy-related proteins were also increased in the renal cortices of lasmiditan-treated AKI mice 3d after I/R injury, whereas fusion-related proteins were increased at 6d after I/R injury.
Conclusion: These data reveal that lasmiditan accelerates renal recovery, restores normal mitochondrial membrane and cristae morphology, decreases excessive mitochondrial fission, and accelerates mitophagy post-AKI in a time-dependent manner, establishing mitochondrial function and recovery from AKI.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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