The APPL1-Rab5 axis restricts NLRP3 inflammasome activation through early endosomal-dependent mitophagy in macrophages

Wu, Kelvin Ka Lok; Long, Kekao; Lin, Huige; Siu, Parco M.; Hoo, Ruby L.C.; Ye, Dewei; Xu, Aimin; Cheng, Kenneth K.Y.

doi:10.1038/s41467-021-26987-1

Cited by 48 publications

(31 citation statements)

References 72 publications

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“…Specifically, APPL1 deficiency decreases the expression of the downstream molecule MYOF in osteoporotic hMSCs to cause lysosomal dysfunction and damage, inhibit autophagy flux, and finally promote hMSC differentiation into adipocytes, resulting in bone marrow adipose tissue hyperplasia and a reduced bone mass. Consistent with the findings from our study, Wu et al [ 53 ] revealed autophagosome accumulation in the absence of APPL1 in mitophagy. Although their research object was macrophages, the results revealed a correlation between APPL1 and the autophagic degradation system.…”

Section: Discussionsupporting

confidence: 93%

Impairment of APPL1/Myoferlin facilitates adipogenic differentiation of mesenchymal stem cells by blocking autophagy flux in osteoporosis

Zhang

Liu

Yuan

et al. 2022

Cell. Mol. Life Sci.

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An imbalance of human mesenchymal stem cells (hMSCs) adipogenic and osteogenic differentiation is crucial in the pathogenesis of osteoporosis, and elucidation of the underlying mechanism is urgently needed. APPL1, an adaptor protein of the adiponectin receptor, was recently shown to be closely related to bone mass. However, the role of APPL1 in the imbalance of hMSC differentiation in osteoporosis is unclear. Therefore, we aimed to explore the mechanisms by which APPL1 alters hMSCs adipogenic differentiation in osteoporosis. Here, we found that APPL1 expression was downregulated in elderly patients with osteoporosis and in mouse osteoporosis model. APPL1 negatively regulated hMSC adipogenic differentiation in vivo and in vitro. Mechanistically, by enhancing ubiquitination-mediated Myoferlin degradation, downregulated APPL1 expression increased the risk of lysosome dysfunction during hMSCs adipogenic differentiation. Lysosomal dysfunction inhibited autophagy flux by suppressing autophagosome degradation and promoted hMSC differentiation towards the adipocyte lineage. Our findings suggest that APPL1/Myoferlin downregulation promoted hMSCs adipogenic differentiation by inhibiting autophagy flux, further impairing the balance of hMSCs adipogenic and osteogenic differentiation in osteoporosis; the APPL1/ Myoferlin axis may be a promising diagnostic and therapeutic target for osteoporosis.

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Section: Discussionsupporting

confidence: 93%

Impairment of APPL1/Myoferlin facilitates adipogenic differentiation of mesenchymal stem cells by blocking autophagy flux in osteoporosis

Zhang

Liu

Yuan

et al. 2022

Cell. Mol. Life Sci.

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“…ASCs in a SIRT3-Dependent Manner. Since dysfunctional or damaged mitochondria are removed by a mechanism called mitophagy to maintain cellular homeostasis, we used LC3 immunofluorescence, MitoTracker Red and DAPI triple staining [30] to detect the effect of irisin and AGEs on mitophagy in ASCs. As shown in Figure 6(a), normal levels of mitophagy could be indicated by colocalization of LC3 and MitoTracker Red.…”

Section: Irisin Mitigates Age-induced Abnormal Mitophagy Inmentioning

confidence: 99%

Irisin Promotes Osteogenesis by Modulating Oxidative Stress and Mitophagy through SIRT3 Signaling under Diabetic Conditions

Jian

Wang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Advanced glycation end products (AGEs) accumulate in the bone tissue of patients with diabetes mellitus, resulting in oxidative stress, poor bone healing, or regeneration. Irisin, a novel exercise-induced myokine, is involved in the regulation of bone metabolism. However, the effects of irisin on adipose-derived stem cell (ASC) osteogenic differentiation and bone healing under diabetic conditions remain poorly understood. ASCs were obtained from inguinal fat of Sprague-Dawley rats and treated with different concentrations of AGEs and irisin. Cell proliferation, apoptosis, and osteogenic differentiation abilities of ASCs were detected. To explore the regulatory role of sirtuin 3 (SIRT3), ASCs were transfected with lentivirus-mediated SIRT3 overexpression or knockdown vectors. Next, we investigated mitochondrial functions, mitophagy, and mitochondrial biogenesis in different groups. Moreover, SOD2 acetylation and potential signaling pathways were assessed. Additionally, a diabetic rat model was used to evaluate the effect of irisin on bone healing in calvarial critical-sized defects (CSDs) in vivo. Our results showed that irisin incubation mitigated the inhibitory effects of AGEs on ASCs by increasing cell viability and promoting osteogenesis. Moreover, irisin modulated mitochondrial membrane potential, intracellular ROS levels, mitochondrial O2·− status, ATP generation, complex I and IV activities, mitophagy, and mitochondrial biogenesis via a SIRT3-mediated pathway under AGEs exposure. Furthermore, in calvarial CSDs of diabetic rats, transplantation of gels encapsulating irisin-pretreated ASCs along with irisin largely enhanced bone healing. These findings suggest that irisin attenuates AGE-induced ASC dysfunction through SIRT3-mediated maintenance of oxidative stress homeostasis and regulation of mitophagy and mitochondrial biogenesis. Thus, our studies shed new light on the role of irisin in promoting the ASC osteogenesis and targeting SIRT3 as a novel therapeutic intervention strategy for bone regeneration under diabetic conditions.

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“…First, we detected the impact of Drp1 knockdown on the expression of the mitochondrial marker proteins Tom20 and Cyto C in BMDMs treated with MSU crystals. They are commonly used as mitochondrial markers to reflect damage mitochondrial clearance and mitophagic rate [ 29 ]. Silence of Drp1 alleviated the elevation of Tom20 and Cyto C protein levels induced by MSU crystals ( Figure 6(a) ).…”

Section: Resultsmentioning

confidence: 99%

“…Mitophagy can mitigate the activation of the NLRP3 inflammasome by regulating mitochondrial quality, maintaining mitochondrial homeostasis and eliminating damaged mitochondria [51][52][53]. Defective mitophagy accelerates the activation of the NLRP3 inflammasome, which may lead to metabolic and autoinflammatory diseases [29,54]. Mito/ autophagy is also involved in MSU crystal-induced NLRP3 inflammasome activation or IL-1β release [54].…”

Section: Discussionmentioning

confidence: 99%

Dynamin-Related Protein 1 Is Involved in Mitochondrial Damage, Defective Mitophagy, and NLRP3 Inflammasome Activation Induced by MSU Crystals

Jiang

Chen

Song

et al. 2022

Oxidative Medicine and Cellular Longevity

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Excessive generation of reactive oxygen species (ROS) has great impacts on MSU crystal-induced inflammation. Drp1-dependent mitochondrial fission is closely associated with mitochondrial ROS levels. However, whether Drp1 signaling contributes to MSU crystal-induced inflammation remains unclear. Mice bone marrow-derived macrophages (BMDMs) were primed with LPS and then stimulated with MSU suspensions for 12 h. The protein levels associated with mitochondrial dynamics, oxidative stress, and mitophagy were detected by Western blot. BMDMs were loaded with MitoTracker Green probe to detect mitochondrial morphology. To measure mitochondrial reactive oxygen species (ROS) and total ROS levels, cells were loaded, respectively, with MitoSOX and DHE probes. The effects of Mito-TEMPO, an antioxidant that targets the mitochondria or DRP1 inhibitor (Mdivi-1) on MSU crystal-induced peritonitis and arthritis mouse models, were evaluated. Our study revealed that MSU crystal stimulation resulted in elevation of mitochondrial fragmentation of BMDMs. Treatment with Mito-TEMPO or Drp1 knockdown significantly ameliorated the mitochondrial damage induced by MSU crystals. BMDMs exposure to MSU crystals increased the expression of auto/mitophagy marker proteins and promoted the fusion of mitophagosomes with lysosomes, leading to accumulation of mitolysosomes. Drp1 knockdown alleviated defective mitophagy and activation of the NLRP3 inflammasome in MSU crystal-treated BMDMs. This study indicates that there is crosstalk between mitochondrial ROS and Drp1 signaling in MSU crystal-induced inflammation. Drp1 signaling is involved in MSU crystal-induced mitochondrial damage, impaired mitophagy and NLRP3 inflammasome activation.

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The APPL1-Rab5 axis restricts NLRP3 inflammasome activation through early endosomal-dependent mitophagy in macrophages

Cited by 48 publications

References 72 publications

Impairment of APPL1/Myoferlin facilitates adipogenic differentiation of mesenchymal stem cells by blocking autophagy flux in osteoporosis

Impairment of APPL1/Myoferlin facilitates adipogenic differentiation of mesenchymal stem cells by blocking autophagy flux in osteoporosis

Irisin Promotes Osteogenesis by Modulating Oxidative Stress and Mitophagy through SIRT3 Signaling under Diabetic Conditions

Dynamin-Related Protein 1 Is Involved in Mitochondrial Damage, Defective Mitophagy, and NLRP3 Inflammasome Activation Induced by MSU Crystals

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