Transferred mitochondria accumulate reactive oxygen species, promoting proliferation

Abstract

Recent studies reveal that lateral mitochondrial transfer, the movement of mitochondria from one cell to another, can affect cellular and tissue homeostasis1,2. Most of what we know about mitochondrial transfer stems from bulk cell studies and have led to the paradigm that functional transferred mitochondria restore bioenergetics and revitalize cellular functions to recipient cells with damaged or non-functional mitochondrial networks3. However, we show that mitochondrial transfer also occurs between cells with functioning endogenous mitochondrial networks, but the mechanisms underlying how transferred mitochondria can promote such sustained behavioral reprogramming remain unclear. We report that unexpectedly, transferred macrophage mitochondria are dysfunctional and accumulate reactive oxygen species in recipient cancer cells. We further discovered that reactive oxygen species accumulation activates ERK signaling, promoting cancer cell proliferation. Pro-tumorigenic macrophages exhibit fragmented mitochondrial networks, leading to higher rates of mitochondrial transfer to cancer cells. Finally, we observe that macrophage mitochondrial transfer promotes tumor cell proliferation in vivo. Collectively these results indicate that transferred macrophage mitochondria activate downstream signaling pathways in a ROS-dependent manner in cancer cells, and provide a model of how sustained behavioral reprogramming can be mediated by a relatively small amount of transferred mitochondria in vitro and in vivo.

Mitochondrial Transplantation promotes protective effector and memory CD4+T cell response duringMycobacterium tuberculosisinfection and diminishes exhaustion and senescence in elderly CD4+T cells

“…Although we enhanced mitochondrial mass in CD4 + T cells, we would not anticipate functional improvements if dysfunctional mitochondria were transferred. Studies examining the impact of intercellular mito-transfer, modulated by tube-nano-tunnels [80], and engulfment of dysfunctional mitochondria [81], demonstrate that immune cell function worsened [80, 81]. This reinforces that the quality of donated mitochondria is equally important in the mitochondrial mass dependent plasticity of aged CD4 + T cells and other immune cells.…”

Astroglia proliferate upon biogenesis of tunneling nanotubes via α-synuclein dependent transient nuclear translocation of focal adhesion kinase

“…In the co-culture experiment, we observed only unidirectional transfer of toxic fragmented mitochondria to their neighbouring cells. Several studies have shown that accumulated ROS with transferred toxic mitochondria could facilitate cell proliferation (Heinke, 2022, Kidwell, Casalini et al, 2023. The observations suggest that astrocytes and astroglia cells share their toxic organelles (lysosomes and mitochondria) with surrounding neighbours to dilute the toxic burden, and the transferred toxic mitochondria may contribute to facilitating proliferation.…”

Intercellular contact and cargo transfer between Müller glia and to microglia precede apoptotic cell clearance in the developing retina

“…If material transfer occurs and is a biologically important process remains to be determined. However, it is worth noting that intercellular transfer from photoreceptors to Müller glia (Hutto et al, 2023), and from macrophages to other cells (Kidwell et al, 2023; Roh-Johnson et al, 2017), have been documented. Nonetheless, the observations from our recordings support that both a “strong-armed” approach by microglia, in which microglia outcompete Müller glia for the apoptotic cell to pull it away, may be possible in addition to a coordinated process in which one or both cells execute a regulated signaling process for the exchange of the YFP+ cells, both of which are yet to be investigated.…”