PINK1 affects mitochondrial oxidative phosphorylation by regulating MFN2 to alleviate diabetic kidney disease
Xiaoyan Pei1, Jie Liu1, Yu Wei1
1Department of Endocrinology, the First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, PR China.
Background:
Diabetic kidney disease (DKD) is widely recognized as a prevalent and major microvascular complication of diabetes mellitus. Mitofusin 2 (MFN2) has been closely linked to the development of diabetes mellitus, yet its precise role in the pathogenesis of DKD remains uncertain. The objective of our current research was to explore the role of MFN2 in the advanced DKD and its underlying molecular pathway. This research was to examine the involvement and molecular pathways of MFN2 in the advancement of DKD.
Methods:
In this study, MFN2 was manipulated in high glucose (HG)-treated HK2 cells to investigate its impact on cell proliferation, apoptosis, and mitochondrial oxidative phosphorylation. Models of MFN2 overexpression or silencing were established in db/db mice as a diabetes model. The alterations in kidney morphology, renal fibrosis severity, macrophage polarization, and related inflammatory factors (tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6], and interleukin-1β [IL-1β]) were evaluated. Furthermore, HK2 cells were co-cultivated with M1-type macrophages to examine the impact of MFN2 expression on macrophage polarization. Subsequently, we delved deeper into the upstream mechanisms utilizing the STRING database.
Results:
Our study identified that MFN2 expression was downregulated in HG-treated HK-2 cells. The overexpression of MFN2 resulted in increased HK2 cell proliferation, improved degree of oxidative phosphorylation, and reduced apoptosis. In db/db mice, MFN2 overexpression exerted a protective effect on DKD-induced nephropathy and fibrosis. Notably, MFN2 overexpression influenced macrophage polarization and modulated expression of related inflammatory factors by promoting mitochondrial oxidative phosphorylation. Additionally, STRING database prediction revealed that PTEN-induced kinase 1 (PINK1) regulated MFN2 expression, which was consistent with MFN2 changes in DKD, and this regulation was associated with DKD progression.
Conclusion:
The role of MFN2 in maintaining mitochondrial function in DKD may be regulated by PINK1 and provides a new potential therapeutic target for DKD.
Insights
Mitofusin 2 (MFN2) protects against diabetic kidney disease (DKD) by improving mitochondrial function and reducing inflammation. PTEN-induced kinase 1 (PINK1) regulates MFN2, offering a potential therapeutic target for DKD.
Area of Science:
- Nephrology
- Molecular Biology
- Mitochondrial Biology
Background:
- Diabetic kidney disease (DKD) is a major complication of diabetes.
- The role of Mitofusin 2 (MFN2) in DKD pathogenesis is not fully understood.
- This study investigates MFN2's role and molecular pathways in advanced DKD.
Purpose of the Study:
- To explore the role of MFN2 in advanced diabetic kidney disease.
- To elucidate the molecular mechanisms underlying MFN2's involvement in DKD.
- To identify potential therapeutic targets for DKD.
Main Methods:
- MFN2 was manipulated in high glucose-treated HK2 cells and db/db mouse models.
- Evaluated cell proliferation, apoptosis, mitochondrial oxidative phosphorylation, kidney morphology, and fibrosis.
- Assessed macrophage polarization and inflammatory factors (TNF-α, IL-6, IL-1β).
- Utilized the STRING database to explore upstream regulatory mechanisms.
Main Results:
- MFN2 expression was downregulated in high glucose conditions.
- MFN2 overexpression enhanced HK2 cell proliferation, improved mitochondrial oxidative phosphorylation, and reduced apoptosis.
- MFN2 overexpression protected against DKD-induced nephropathy and fibrosis in db/db mice.
- MFN2 modulated macrophage polarization and inflammatory factors via mitochondrial oxidative phosphorylation.
- PTEN-induced kinase 1 (PINK1) was identified as a regulator of MFN2 in DKD.
Conclusions:
- MFN2 plays a protective role in DKD by maintaining mitochondrial function.
- PINK1 regulates MFN2's function in DKD.
- MFN2, regulated by PINK1, represents a potential therapeutic target for diabetic kidney disease.
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