PINK1 deficiency impairs osteoblast differentiation through aberrant mitochondrial homeostasis

Abstract

Background PTEN-induced kinase 1 (PINK1) is a serine/threonine-protein kinase in mitochondria that is critical for mitochondrial quality control. PINK1 triggers mitophagy, a selective autophagy of mitochondria, and is involved in mitochondrial regeneration. Although increments of mitochondrial biogenesis and activity are known to be crucial during differentiation, data regarding the specific role of PINK1 in osteogenic maturation and bone remodeling are limited. Methods We adopted an ovariectomy model in female wildtype and Pink1−/− mice. Ovariectomized mice were analyzed using micro-CT, H&E staining, Masson’s trichrome staining. RT-PCR, western blot, immunofluorescence, alkaline phosphatase, and alizarin red staining were performed to assess the expression of PINK1 and osteogenic markers in silencing of PINK1 MC3T3-E1 cells. Clinical relevance of PINK1 expression levels was determined via qRT-PCR analysis in normal and osteoporosis patients. Results A significant decrease in bone mass and collagen deposition was observed in the femurs of Pink1−/− mice after ovariectomy. Ex vivo, differentiation of osteoblasts was inhibited upon Pink1 downregulation, accompanied by impaired mitochondrial homeostasis, increased mitochondrial reactive oxygen species production, and defects in mitochondrial calcium handling. Furthermore, PINK1 expression was reduced in bones from patients with osteoporosis, which supports the practical role of PINK1 in human bone disease. Conclusions In this study, we demonstrated that activation of PINK1 is a requisite in osteoblasts during differentiation, which is related to mitochondrial quality control and low reactive oxygen species production. Enhancing PINK1 activity might be a possible treatment target in bone diseases as it can promote a healthy pool of functional mitochondria in osteoblasts.

UCHL1 Impairs Periodontal Ligament Stem Cell Osteogenesis in Periodontitis

“…Growing evidence has indicated that UCHL1 could function via inhibiting mitophagy (Cerqueira et al 2020; Ham et al 2021), which is a positive regulator of osteogenesis (Pei et al 2018; Lee et al 2021). Hence, we explored whether mitophagy was involved in the UCHL1-regulated osteogenesis.…”

“…Mechanistically, we have demonstrated that UCHL1 suppressed PDLSC osteogenesis through inhibiting mitophagy in periodontitis-associated inflammation. Mitophagy, anorganelle-specific autophagy pathway to remove dysfunctional or superfluous mitochondria (Palikaras et al 2018), has been recently identified as a critical role in osteogenesis, with numerous studies reporting that the activation of PINK1/Parkin-mediated mitophagy was a requisite in osteogenic differentiation (Pei et al 2018; Lee et al 2021). This corresponded to our results of the effects of mitophagy inhibitor on PDLSC osteogenesis.…”

Mitochondrial quality control and its role in osteoporosis

“…Lee ( 53 ) found that PINK1 expression was reduced in OP patients. Bone mass was significantly reduced in an ovariectomized mouse model with PINK1 gene deficiency.…”

Mitophagy—A New Target of Bone Disease

“…Accumulating evidence suggests that aberrant mitophagy plays a key role in stem cell differentiation and in bone metabolism disorders [ 12 , 118 ]. Recent studies have found that mitophagy is involved in the regulation of OP [ 119 , 120 ], which may be related to signals such as phosphoinositide 3-kinase (PI3K) [ 115 ] and Pink1 [ 121 ] (as shown in Figure 2 ).…”

“…Activation of PINK1 is necessary during osteoblast differentiation, which is associated with mitochondrial quality control and low reactive oxygen species production. Lee et al [ 121 ] found that the expression of endogenous PINK1 is increased during osteogenic differentiation. Downregulation of PINK1 impairs mitochondrial homeostasis, increases mitochondrial ROS generation, and inhibits osteoblast differentiation.…”