The tethering function of mitofusin2 controls osteoclast differentiation by modulating the Ca2+-NFATc1 axis.
Anna BallardRong ZengAllahdad ZareiChristine ShaoLinda CoxHui YanAntonietta FrancoGerald W DornRoberta FaccioDeborah J VeisPublished in: The Journal of biological chemistry (2020)
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.
Keyphrases
- bone loss
- endoplasmic reticulum
- nuclear factor
- oxidative stress
- toll like receptor
- transcription factor
- poor prognosis
- signaling pathway
- cell death
- high fat diet induced
- gene expression
- immune response
- lps induced
- endothelial cells
- bone mineral density
- binding protein
- reactive oxygen species
- bone marrow
- high glucose
- cell cycle arrest
- wild type
- stem cells
- adipose tissue
- nlrp inflammasome
- skeletal muscle
- diabetic rats
- genome wide
- gestational age
- cell therapy