Endoplasmic reticulum mediates mitochondrial transfer within the osteocyte dendritic network

Abstract

Mitochondrial transfer plays a crucial role in the regulation of tissue homeostasis and resistance to cancer chemotherapy. Osteocytes have interconnecting dendritic networks and are a model to investigate its mechanism. We have demonstrated, in primary murine osteocytes with photoactivatable mitochondria (PhAM)floxed and in MLO-Y4 cells, mitochondrial transfer in the dendritic networks visualized by high-resolution confocal imaging. Normal osteocytes transferred mitochondria to adjacent metabolically stressed osteocytes and restored their metabolic function. The coordinated movement and transfer of mitochondria within the dendritic network rely on contact between the endoplasmic reticulum (ER) and mitochondria. Mitofusin 2 (Mfn2), a GTPase that tethers ER to mitochondria, predominantly mediates the transfer. A decline in Mfn2 expression with age occurs concomitantly with both impaired mitochondrial distribution and transfer in the osteocyte dendritic network. These data show a previously unknown function of ER-mitochondrial contact in mediating mitochondrial transfer and provide a mechanism to explain the homeostasis of osteocytes.

Intercellular mitochondrial transfer as a means of tissue revitalization

“… 72 Recently, our group verified that the distribution of mitochondria in primary osteocyte dendrites decreased with aging. 73 Furthermore, we found that intercellular mitochondrial transfer also occurs within the osteocyte dendritic network and that the transferred mitochondria restored the cellular metabolism in stressed osteocytes without functional mitochondria. 73 In addition, we found that ER–mitochondria contact plays a crucial role in mediating the transfer of mitochondria between osteocytes.…”

“… 73 Furthermore, we found that intercellular mitochondrial transfer also occurs within the osteocyte dendritic network and that the transferred mitochondria restored the cellular metabolism in stressed osteocytes without functional mitochondria. 73 In addition, we found that ER–mitochondria contact plays a crucial role in mediating the transfer of mitochondria between osteocytes. 73 Intriguingly, mitofusion 2 (Mfn2), a tethering protein involved in ER–mitochondria contact, was also reduced in aging osteocytes, 73 which might impair the transfer of mitochondria between aged osteocytes.…”

“… 73 In addition, we found that ER–mitochondria contact plays a crucial role in mediating the transfer of mitochondria between osteocytes. 73 Intriguingly, mitofusion 2 (Mfn2), a tethering protein involved in ER–mitochondria contact, was also reduced in aging osteocytes, 73 which might impair the transfer of mitochondria between aged osteocytes. Thus, it is highly plausible that mitochondrial transfer within the osteocyte dendritic network participates in maintaining the viability of osteocytes and regulating the bone homeostasis during aging.…”

“…1b ). 73 By selectively blocking the formation of TNTs via the actin-binding toxin, cytochalasin B, at nanomolar concentration (350 nM), which had negligible effects on endocytosis and phagocytosis activities, the organelle transfer between cells was dramatically reduced. 118

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Epigenetic Regulation of Skeletal Tissue Integrity and Osteoporosis Development

“…Dysfunctional mitochondria are known to overproduce reactive oxygen radicals, destabilizing proteins or activating apoptosis programs in osteoblastic cells within the diabetes and age-mediated osteoporotic skeleton [ 18 , 19 ]. Advanced glycation end-products induce endoplasmic reticulum stress, accelerating osteoblast apoptosis in senile vertebrae [ 20 ]. The declined transportation capacity of the endoplasmic reticulum also decreases the transfer and distribution of mitochondria, suppressing intracellular homeostasis in senescent osteocytes [ 21 ].…”