PGC-1α-mediated mitochondrial homeostasis imbalance aggravated gingival lesions of diabetic periodontitis by disrupting ECM remodeling of human gingival fibroblast

Abstract

Diabetic periodontitis (DP) usually has more severe clinical symptoms compared with chronic periodontitis (CP), especially the worsened gingival lesions. Mitochondrial homeostasis plays an important role in both diabetes and periodontitis, and some studies have already confirmed its role in DP. However, there are few reports on whether mitochondrial homeostasis is involved in regulating DP gingival lesions. In this study, we focused on the pathological changes of the gingival connective tissues from DP and identified the extracellular matrix (ECM) pathway as the key regulatory pathway. Additionally, we found that the pathological changes in DP gingiva were accompanied by significant alterations in the morphology and structure of cellular mitochondria. We discovered that the regulatory molecule PGC-1α related to mitochondrial quality control (MQC) was significantly downregulated in DP group through RNA sequencing. Furthermore, by using high glucose and LPS co-stimulation to simulate DP environment in vitro, we confirmed the changes in ECM synthesis and remodeling of human gingival fibroblasts (HGFs), accompanied with the abnormal mitochondrial morphology, structure and function, including the presence of internal vacuolation, the increased area and perimeter, the loss of cristae, as well as the increased mtROS, the decreased ATP, mitochondrial membrane potential, and the mtDNA copy number, and even the reduced number of mitochondria in HGFs, which suggesting the changes of mitochondrial homeostasis. Moreover, we verified that upregulating PGC-1α could reverse the above phenomena in HGFs. Finally, periodontal injection of PGC-1α agonists (ZLN005) was found to ameliorate the abnormal ECM synthesis and remodeling by improving mitochondrial homeostasis in DP rats, demonstrating a significant therapeutic effect on DP gingival lesions and moderating the progression of DP. In conclusion, our study proposed the possible therapeutic effect of PGC-1α-mediated mitochondrial homeostasis in the aggravated gingival lesions of DP, providing new ideas for the clinical treatment of DP.