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Selenoprotein H targets MTCH2 to regulate MFN2-dependent mitochondrial quality control to alleviate acute kidney
Dongliu Luo1, Yaning Qiu2, Jiahong Chu2
1College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China; College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471023, China.
Introduction:
Mitochondrial dysfunction is recognized as a pivotal event in the pathogenesis of acute kidney injury (AKI). Selenoprotein (SelH), a mammalian selenoprotein, is extensively involved in regulating of diseases associated with mitochondrial dysfunction. However, its regulatory role in mitochondrial quality control during AKI remains unclear.
Objectives:
This study aims to explore the impact of SelH on AKI and potential regulatory mechanisms of SelH in AKI.
Methods:
In vivo, a cisplatin (CP)-induced AKI model was established using SelH knockout mice to evaluate renal injury. Additionally, co-immunoprecipitation (Co-IP). combined with mass spectrometry, Co-IP assays, laser confocal microscopy, and molecular docking were employed to identify proteins interacting with SelH. In vitro, SelH/mitochondrial carrier homolog 2 (MTCH2) knockdown and overexpression models were constructed in HEK293t cells. Indicators related to oxidative stress, mitochondrial biogenesis, mitochondrial dynamics, mitophagy, and apoptosis were analyzed.
Results:
MTCH2 was identified as a potential interacting partner of SelH. Deficiency of renal SelH directly triggered oxidative stress, impaired mitochondrial biogenesis, disrupted mitochondrial dynamics, enhanced mitophagy, and promoted apoptosis. In HEK293t cells, SelH targeted MTCH2 to regulate mitofusin 2 (MFN2), thereby promoting mitochondrial fusion, alleviating mitochondrial dysfunction, maintaining mitochondrial quality control (MQC) homeostasis, and reducing renal oxidative damage and apoptosis.
Conclusion:
The results showed that SelH targets the MTCH2/MFN2 aixs to maintain MQC balance, alleviate oxidative stress and cell apoptosis induced by AKI. This study not only supplements kidney specific regulatory targets for the field of mitochondrial medicine but also suggests that SelH could serve as a potential molecule for proactive medicine intervention in AKI, providing experimental evidence for the early intervention of AKI.
Insights
Selenoprotein H (SelH) protects against acute kidney injury (AKI) by maintaining mitochondrial quality control. SelH targets MTCH2 to regulate MFN2, reducing oxidative stress and apoptosis in AKI.
Area of Science:
- Nephrology
- Mitochondrial Medicine
- Cellular Biology
Background:
- Mitochondrial dysfunction is central to acute kidney injury (AKI) pathogenesis.
- Selenoprotein H (SelH) is implicated in diseases involving mitochondrial dysfunction, but its role in AKI's mitochondrial quality control (MQC) is unknown.
Purpose of the Study:
- To investigate the impact of SelH on AKI.
- To elucidate the regulatory mechanisms of SelH in AKI.
Main Methods:
- Established a cisplatin-induced AKI mouse model using SelH knockout mice.
- Utilized co-immunoprecipitation, mass spectrometry, laser confocal microscopy, and molecular docking to identify SelH interacting proteins.
- Constructed SelH/mitochondrial carrier homolog 2 (MTCH2) knockdown and overexpression models in HEK293t cells to analyze oxidative stress, mitochondrial biogenesis, dynamics, mitophagy, and apoptosis.
Main Results:
- Identified MTCH2 as a SelH interacting partner.
- Renal SelH deficiency exacerbated oxidative stress, impaired mitochondrial biogenesis, disrupted mitochondrial dynamics, enhanced mitophagy, and promoted apoptosis.
- In vitro, SelH targeted MTCH2 to regulate mitofusin 2 (MFN2), promoting mitochondrial fusion and alleviating mitochondrial dysfunction.
Conclusions:
- SelH maintains MQC balance by targeting the MTCH2/MFN2 axis, alleviating AKI-induced oxidative stress and apoptosis.
- SelH represents a potential therapeutic target for proactive AKI intervention.
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