PINK1/Parkin-mediated mitophagy inhibits osteoblast apoptosis induced by advanced oxidation protein products

Abstract

Osteoblast apoptosis plays an important role in age-related bone loss and osteoporosis. Our previous study revealed that advanced oxidation protein products (AOPPs) could induce nicotinamide adenine dinucleotide phosphate oxidase (NOX)-derived reactive oxygen species (ROS) production, cause mitochondrial membrane potential (ΔΨm) depolarization, trigger the mitochondria-dependent intrinsic apoptosis pathway, and lead to osteoblast apoptosis and ultimately osteopenia and bone microstructural destruction. In this study, we found that AOPPs also induced mitochondrial ROS (mtROS) generation in osteoblastic MC3T3-E1 cells, which was closely related to NOX-derived ROS, and aggravated the oxidative stress condition, thereby further promoting apoptosis. Removing excessive ROS and damaged mitochondria is the key factor in reversing AOPP-induced apoptosis. Here, by in vitro studies, we showed that rapamycin further activated PINK1/Parkin-mediated mitophagy in AOPP-stimulated MC3T3-E1 cells and significantly alleviated AOPP-induced cell apoptosis by eliminating ROS and damaged mitochondria. Our in vivo studies revealed that PINK1/Parkin-mediated mitophagy could decrease the plasma AOPP concentration and inhibit AOPP-induced osteoblast apoptosis, thus ameliorating AOPP accumulation-related bone loss, bone microstructural destruction and bone mineral density (BMD) loss. Together, our study indicated that therapeutic strategies aimed at upregulating osteoblast mitophagy and preserving mitochondrial function might have potential for treating age-related osteoporosis.

NDP52 SUMOylation contributes to low‐dose X‐rays‐induced cardiac hypertrophy through PINK1/Parkin‐mediated mitophagy via MUL1/SUMO2 signalling

“…Through binding to the mitochondrial outer membrane, PINK1 can translocate to the inner mitochondrial membrane for the proteolytic degradation of presenselin associated, rhomboid‐like (PARL) protease. It has been reported that the ubiquitinational degradation of mitochondrial proteins depends on the accumulation of PINK1 and the interaction of PINK1 with the E3 ubiquitin ligase Parkin, which is involved in multiple cardiovascular diseases (Gong et al, 2015; W. Li et al, 2023; Lu et al, 2022). Our results showed that activation of the PINK1/Parkin pathway further promoted impaired cardiac functions under low‐dose X‐ray conditions, which was mechanistically accompanied by colocalization between LC3 and mitoTracker.…”

“…The present in vivo study of SD rats showed that low‐dose X‐ray promoted cardiac hypertrophy was facilitated under PINK1/Parkin pathway agonist PARL‐IN‐1 treatment, suggesting the strong association between PINK1/Parkin‐mediated mitophagy and cardiac hypertrophy induced by low‐dose X‐rays. PINK1 is a serine/threonine kinase primarily located on the mitochondrial outer membrane that plays an important regulatory role in mitophagy by recruiting the E3 ubiquitin ligase Parkin (Gan et al, 2022; W. Li et al, 2023). Through binding to the mitochondrial outer membrane, PINK1 can translocate to the inner mitochondrial membrane for the proteolytic degradation of presenselin associated, rhomboid‐like (PARL) protease.…”

“…However, the regulatory signalling pathway through which low‐dose X‐rays induce mitophagy and trigger cardiac hypertrophy remains unclear. The ubiquitin kinase PTEN‐induced kinase 1 (PINK1)/Parkin pathway plays a crucial role in inducing damaged mitochondria to enter the autophagic flux and promoting mitophagy (W. Li et al, 2023). PINK1 is a serine/threonine kinase located in the outer mitochondrial membrane that recruits the E3 ubiquitin ligase Parkin and binds to the autophagy‐related protein LC3, thereby initiating mitophagy (Lin et al, 2022).…”

The Potential of Natural Compounds Regulating Autophagy in the Treatment of Osteoporosis

“… 38 In age-related OP, a large number of advanced oxidation protein products (AOPPs) promote the production of mitochondrial ROS (mROS), which aggravates oxidative stress and promotes OBs apoptosis, while PINK1/Parkin-mediated mitophagy can eliminate excessive mROS and damaged mitochondria to reverse AOPP-induced OBs apoptosis. 104 Excess ROS can activate mitophagy, which is an important mechanism for controlling mitochondrial quality and cell homeostasis. Interestingly, when dibutyl phthalate (DBP) treated OBs, a large amount of ROS was generated and accompanied by the activation of mitophagy.…”

Mitophagy in atherosclerosis: from mechanism to therapy

“…RBR E3 ubiquitin-protein ligase cause mitochondrial dysfunction, muscle degeneration, and decreased longevity (20,21). PINK1/ Parkin-mediated mitophagy may control cell survival or death by eliminating damaged mitochondria (22)(23)(24). Under normal conditions, PINK1 enters the mitochondria through the translocase of the outer mitochondrial membrane (TOMM) complex, which is found in the outer mitochondrial membrane (OMM), and the translocase of the inner mitochondrial membrane 23 (TIMM23), and then moves on to the inner mitochondrial membrane (IMM) translocase complex (25).…”