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GLIS1 alleviates cell senescence and renal fibrosis through PGC1-α mediated mitochondrial quality control in kidney
Li Xu1, Jiao Wang2, Hongyuan Yu3
1Department of Laboratory Medicine, The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524003, China.
Abstract:
Mitochondrial dysfunction is implied as a crucial factor in age-related chronic kidney disease. It is confirmed that Gli-like transcription factor 1 (GLIS1) is involved in age-related renal fibrosis, however, the correlation between mitochondrial disturbances and GLIS1-driven kidney aging are not clearly clarified. Thus, we investigated the regulatory mechanism of GLIS1 in the homeostasis of mitochondrial quality control both in vivo and in vitro. The lower expression of GLIS1 was identified in natural and accelerated kidney aged models, accompanied by the dysfunctions of mitochondrial quality control, including enhanced mitochondrial fission, reduced mitochondrial biogenesis and mitophagy, whereas, GLIS1 could maintain mitochondrial stability by interacting with peroxisome proliferator-activated receptor γ coactivator-1α (PGC1-α). Additionally, the over-expressed GLIS1 inhibited extracellular matrix accumulation and alleviated renal fibrosis while siGLIS1 inhibited PGC1-α transcription, as well as affecting its mitochondria-protective functions. Collectively, we demonstrated that GLIS1 mediated mitochondrial quality control through targeting PGC1-α in kidney aging, which might be a promising therapeutic target for attenuating cell senescence and age-related renal fibrosis.
Insights
Glial-like transcription factor 1 (GLIS1) maintains kidney health during aging by regulating mitochondrial stability. Lower GLIS1 levels impair mitochondrial function and promote kidney fibrosis, suggesting GLIS1 as a therapeutic target.
Area of Science:
- Nephrology
- Gerontology
- Mitochondrial Biology
Background:
- Mitochondrial dysfunction is a key factor in age-related chronic kidney disease (CKD).
- Glial-like transcription factor 1 (GLIS1) is linked to age-related renal fibrosis, but its role in mitochondrial homeostasis during kidney aging is unclear.
- Understanding GLIS1's regulatory mechanism in mitochondrial quality control is crucial for addressing kidney aging.
Purpose of the Study:
- To investigate the role of GLIS1 in maintaining mitochondrial quality control during kidney aging.
- To elucidate the mechanism by which GLIS1 influences mitochondrial stability and renal fibrosis.
- To explore GLIS1 as a potential therapeutic target for age-related kidney disease.
Main Methods:
- In vivo and in vitro studies using natural and accelerated kidney aging models.
- Analysis of GLIS1 expression levels in aged kidney tissues.
- Investigation of GLIS1 interaction with peroxisome proliferator-activated receptor γ coactivator-1α (PGC1-α).
- Assessment of mitochondrial dynamics (fission, biogenesis, mitophagy) and extracellular matrix accumulation.
Main Results:
- Lower GLIS1 expression was observed in aged kidney models, correlating with impaired mitochondrial quality control (increased fission, reduced biogenesis and mitophagy).
- GLIS1 interacts with PGC1-α to maintain mitochondrial stability.
- Overexpression of GLIS1 reduced extracellular matrix accumulation and alleviated renal fibrosis.
- Silencing GLIS1 (siGLIS1) inhibited PGC1-α transcription and its protective functions.
Conclusions:
- GLIS1 plays a critical role in mediating mitochondrial quality control through PGC1-α in kidney aging.
- GLIS1 is a potential therapeutic target for mitigating cell senescence and age-related renal fibrosis.
- Targeting GLIS1 may offer a novel strategy for treating chronic kidney disease associated with aging.
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