PINK1‐mediated mitophagy reduced inflammatory responses to Porphyromonas gingivalis in macrophages

Abstract

ObjectiveMitochondria are strained by microbial stimuli in the periodontal niche. Damaged mitochondria are cleared by mitophagy. The purpose of the study was to explore whether mitophagy participated in the progress of periodontitis and whether activation of mitophagy can inhibit inflammatory responses to bacterial infection in macrophages.MethodsMitophagy‐related genes were measured in the healthy and inflamed human gingiva. Bone marrow‐derived macrophages (BMDMs) were infected with Porphyromonas gingivalis. Dexmedetomidine, urolithin A, and resveratrol were used to activate mitophagy, while small interference RNA was utilized to knock down PTEN‐induced putative protein kinase 1 (PINK1). Activation of mitophagy‐related genes and colocalization of them were detected by Western blot and confocal imaging. Damages of mitochondria, accumulation of mitochondrial reactive oxygen species (mtROS), and production of IL‐1β, IL‐6, and TNF‐α were measured.ResultsLevels of mitophagy‐related genes were decreased in inflamed periodontal tissues and P. gingivalis‐infected BMDMs. Dexmedetomidine, urolithin A, and resveratrol activated mitophagy, leading to reduced mitochondria damages, decreased mtROS generation, and inhibited IL‐1β, IL‐6, and TNF‐α production. PINK1 knockdown reduced dexmedetomidine, urolithin A, and resveratrol‐induced anti‐inflammatory effect.ConclusionInhibited mitophagy participated in the progress of periodontitis. Activation of mitophagy may become a therapeutic target during the progress of periodontitis by reducing mtROS.

Ultrastructural localization and characterization of P. gingivalis gingipain virulence factors in the substantia nigra of brains with and without Parkinson’s disease

“…In addition, P. gingivalis infection has been shown to impair the expression of the canonical PD-related proteins PTEN-induced putative protein kinase 1 (PINK1) and Parkin, two proteins critically involved in clearing damaged or dysfunctional mitochondria by mitophagy. 44 Mutations in PINK1 and PARK2 (the gene for Parkin) are involved in PD pathogenesis. 45 In P. gingivalisinfected bone marrow-derived macrophages, infection resulted in decreased mRNA transcription and protein expression of both PINK1 and Parkin, leading to an inhibition of mitophagy and a resultant accumulation of damaged mitochondria and reactive oxygen species (ROS).…”

“…45 In P. gingivalisinfected bone marrow-derived macrophages, infection resulted in decreased mRNA transcription and protein expression of both PINK1 and Parkin, leading to an inhibition of mitophagy and a resultant accumulation of damaged mitochondria and reactive oxygen species (ROS). 44 Further research is needed to determine the mechanism by which P. gingivalis manipulates PINK1 and Parkin expression, and if this inhibitory effect on mitophagy can occur in dopaminergic neurons.…”

The role of mitochondrial dysfunction in periodontitis: From mechanisms to therapeutic strategy

“…A recent study analyzed the clinical specimens of gingival tissues from healthy and periodontitis patients and observed that the expression of PINK1, parkin and microtubuleassociated proteins light chain 3 (LC3) was significantly downregulated. 51 However, the PINK1 expression of hGFs exposed to different doses was found to be up-regulated or down-regulated. 52 It has been reported that PINK1-mediated mitophagy affects the development of disease through mitochondria-dependent apoptosis pathway 53 or inflammation regulation, 54 and it also exists in the pathogenesis of periodontitis.…”

“…It resides in the outer mitochondrial membrane (OMM) of the mitochondria, initially lacking in expression, but would accumulate in the OMM during mitochondrial damage, transferring parkin from the cytoplasm to the OMM and triggering mitophagy. A recent study analyzed the clinical specimens of gingival tissues from healthy and periodontitis patients and observed that the expression of PINK1, parkin and microtubule‐associated proteins light chain 3 (LC3) was significantly down‐regulated 51 . However, the PINK1 expression of hGFs exposed to different doses was found to be up‐regulated or down‐regulated 52 .…”

“…The rescue experiment verified that PINK1 regulated the expression level of apoptotic signal caspase 9, suggesting that PINK1/parkin‐mediated mitophagy protects diabetic periodontitis cells from apoptosis. In terms of inflammatory regulation, Jiang et al 51 constructed a model of Pg‐induced macrophage inflammatory injury at the cellular level. Results revealed that the increased expression of pro‐inflammatory factors and mtROS depended on the decreased expression levels of PINK1, parkin and LC3.…”