Mitofusin 2, a mitochondria-ER tethering protein, facilitates osteoclastogenesis by regulating the calcium-calcineurin-NFATc1 axis

Jung, Suhan; Kwon, Jun-Oh; Kim, Min Kyung; Song, Min Kyoung; Kim, Bongjun; Lee, Zang Hee; Kim, Hong-Hee

doi:10.1016/j.bbrc.2019.06.017

Cited by 11 publications

(6 citation statements)

References 34 publications

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“…Similar blunting of SOCE was found in C2C12 myoblasts with MFN2 knockdown (36). Interestingly, our dcKOs showed higher basal cytoplasmic Ca 2ϩ , whereas MFN2-depleted C2C12 cells and BMMs had lower basal cytoplasmic Ca 2ϩ than controls (36,37). It is possible that the presence of MFN1 in the experiments with MFN2 knockdown plays a role in basal levels, whereas MFN2 is more important for SOCE regulation.…”

Section: Mfn2 Directs Osteoclastogenesissupporting

confidence: 78%

The tethering function of mitofusin2 controls osteoclast differentiation by modulating the Ca2+–NFATc1 axis

Ballard

Zeng

Zarei

et al. 2020

Journal of Biological Chemistry

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Dynamic regulation of the mitochondrial network by mitofusins (MFNs) modulates energy production, cell survival, and many intracellular signaling events, including calcium handling. However, the relative importance of specific mitochondrial functions and their dependence on MFNs vary greatly among cell types. Osteoclasts have many mitochondria, and increased mitochondrial biogenesis and oxidative phosphorylation enhance bone resorption, but little is known about the mitochondrial network or MFNs in osteoclasts. Because expression of each MFN isoform increases with osteoclastogenesis, we conditionally deleted MFN1 and MFN2 (double conditional KO (dcKO)) in murine osteoclast precursors, finding that this increased bone mass in young female mice and abolished osteoclast precursor differentiation into mature osteoclasts in vitro. Defective osteoclastogenesis was reversed by overexpression of MFN2 but not MFN1; therefore, we generated mice lacking only MFN2 in osteoclasts. MFN2-deficient female mice had increased bone mass at 1 year and resistance to Receptor Activator of NF-κB Ligand (RANKL)-induced osteolysis at 8 weeks. To explore whether MFN-mediated tethering or mitophagy is important for osteoclastogenesis, we overexpressed MFN2 variants defective in either function in dcKO precursors and found that, although mitophagy was dispensable for differentiation, tethering was required. Because the master osteoclastogenic transcriptional regulator nuclear factor of activated T cells 1 (NFATc1) is calcium-regulated, we assessed calcium release from the endoplasmic reticulum and store-operated calcium entry and found that the latter was blunted in dcKO cells. Restored osteoclast differentiation by expression of intact MFN2 or the mitophagy-defective variant was associated with normalization of store-operated calcium entry and NFATc1 levels, indicating that MFN2 controls mitochondrion–endoplasmic reticulum tethering in osteoclasts.

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Section: Mfn2 Directs Osteoclastogenesissupporting

confidence: 78%

The tethering function of mitofusin2 controls osteoclast differentiation by modulating the Ca2+–NFATc1 axis

Ballard

Zeng

Zarei

et al. 2020

Journal of Biological Chemistry

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“…The role of Mfns in osteoclasts has been previously reported [24,25]. Dual deletion of Mfn1 and Mfn2 in the osteoclast lineage leads to increased bone mass in female mice in vivo [25].…”

Section: Discussionmentioning

confidence: 99%

“…Loss of Mfn2 also leads to increased bone mass in vivo [25]. Mechanically, Mfn2 mediates connections between endoplasmic reticulum and mitochondria, which generates large fluctuations in cytoplasmic Ca 2+ that drives NFATc1 activation [24,25]. Since Mfn2 acts as the molecular tether that connects mitochondria to the endo/sarcoplasmic reticulum, in addition to promoting mitochondrial fusion [26], it is unclear whether the mitochondrial fusion function of Mfn2 plays some role during osteoclast formation.…”

Section: Discussionmentioning

confidence: 99%

Dynamin‐related protein 1 positively regulates osteoclast differentiation and bone loss

et al. 2020

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Dynamin-related protein 1 (DRP1) is a mitochondrial membrane GTPase and regulates mitochondrial fission. In this study, we found that the cytokine RANKL increased the expression of DRP1 and its receptor proteins, Fis1, Mid49, and Mid 51, during osteoclast formation in mouse bone marrowderived macrophages. Inactivation of the kinase GSK3b appeared to induce DRP1 expression. DRP1 knockdown or the DRP1 inhibitor Mdivi1 suppressed osteoclast differentiation via downregulation of c-Fos and NFATc1, the key transcription factor for osteoclast formation. Finally, the DRP1 inhibitor suppressed lipopolysaccharide-induced osteoclast formation in a calvarial model and ovariectomy-induced bone loss in vivo. Taken together, our data demonstrate that DRP1 positively contributes to RANKL-induced osteoclast differentiation by regulating the c-Fos-NFATc1 axis, suggesting the importance of mitochondrial DRP1 in osteoclastogenesis.

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“…In line with these observations, osteoclasts are multinucleated giant cells that contain a very high density of mitochondria, and increased mitochondria biogenesis and oxidative phosphorylation increase bone resorption. Interestingly enough, very recent studies revealed that mitofusin 2 facilitates osteoclastogenesis by modulating calcium -calcineurin -NFATc1 (Nuclear factor of activated T-cell cytoplasm1); thus, it is tempting to propose that mitochondria function might be damaged in CTNS deficient osteoclasts [37,38]. The study of proximal tubular kidney cells obtained from healthy donors and patients with cystinosis reveals that cystinosin deficiency is associated with altered mammalian target of rapamycin complex 1 (mTORC1) signaling, characterized by abnormal lysosomal retention of mTORC1 during starvation followed by delayed reactivation of mTORC1 [39].…”

Section: Bone Disease and Nephropathic Cystinosis: A Functional Impairment Of Both Osteoblasts And Osteoclastsmentioning

confidence: 99%

Bone Disease in Nephropathic Cystinosis: Beyond Renal Osteodystrophy

Machuca-Gayet

Quinaux

Bertholet‐Thomas

et al. 2020

IJMS

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Patients with chronic kidney disease (CKD) display significant mineral and bone disorders (CKD-MBD) that induce significant cardiovascular, growth and bone comorbidities. Nephropathic cystinosis is an inherited metabolic disorder caused by the lysosomal accumulation of cystine due to mutations in the CTNS gene encoding cystinosin, and leads to end-stage renal disease within the second decade. The cornerstone of management relies on cysteamine therapy to decrease lysosomal cystine accumulation in target organs. However, despite cysteamine therapy, patients display severe bone symptoms, and the concept of “cystinosis metabolic bone disease” is currently emerging. Even though its exact pathophysiology remains unclear, at least five distinct but complementary entities can explain bone impairment in addition to CKD-MBD: long-term consequences of renal Fanconi syndrome, malnutrition and copper deficiency, hormonal disturbances, myopathy, and intrinsic/iatrogenic bone defects. Direct effects of both CTNS mutation and cysteamine on osteoblasts and osteoclasts are described. Thus, the main objective of this manuscript is not only to provide a clinical update on bone disease in cystinosis, but also to summarize the current experimental evidence demonstrating a functional impairment of bone cells in this disease and to discuss new working hypotheses that deserve future research in the field.

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Mitofusin 2, a mitochondria-ER tethering protein, facilitates osteoclastogenesis by regulating the calcium-calcineurin-NFATc1 axis

Cited by 11 publications

References 34 publications

The tethering function of mitofusin2 controls osteoclast differentiation by modulating the Ca2+–NFATc1 axis

The tethering function of mitofusin2 controls osteoclast differentiation by modulating the Ca2+–NFATc1 axis

Dynamin‐related protein 1 positively regulates osteoclast differentiation and bone loss

Bone Disease in Nephropathic Cystinosis: Beyond Renal Osteodystrophy

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