Extrusion of mitochondria: Garbage clearance or cell–cell communication signals?

Abstract

Mitochondria are dynamic organelles that regulate various intracellular signaling pathways, including the mechanisms of programmed cell death, differentiation, inflammation, and so on. Mitochondria may be extruded as membrane enveloped or as free organelles during developmental processes, inflammatory activation, and in the process of “garbage clearance” of damaged mitochondria in postmitotic cells. Extracellular mitochondria can be engulfed by immune and nonimmune cells and trigger intracellular signaling leading to an inflammatory response. At the same time, it was reported that the release of extracellular vesicles containing mitochondria from mesenchymal stem cells contributes to their therapeutic anti‐inflammatory effects. Numerous studies claim that engulfed mitochondria improve cellular bioenergetics, but this assumption requires further investigation. This review aims at a critical discussion of the mechanisms of mitochondrial extrusion in mammals, the reception of mitochondrial components, and the responses of recipient cells to extracellular mitochondria.

Do Extracellular Vesicles Derived from Mesenchymal Stem Cells Contain Functional Mitochondria?

“…EV formation can be very powerful, as a result of which newly formed vesicles can be observed in the environment of MSC, forming clusters of EV (Figure 1C). The second rather speculative mechanism can be reduced to the intracellular formation of vesicles, as a result of which they concentrate in the form of certain depots (Figure 1D), which can subsequently be ejected from cells like the described process of mitochondria ejection from cells [13,22,23]. A key question remains: how functional are the mitochondria removed from the cell in this way?…”

“…The fundamental and practical aspects of vesicle biology and medicine have become very popular topics, confirming intercellular, and maybe even inter-organ communication [8]. Much attention is paid to this communication, and in particular, the discovery of the transfer of mitochondria between cells aroused the particular interest of researchers [9][10][11][12][13][14][15] resulting in multidirectional responses of the recipient cells [16].…”

Microvesicle release from inner segments of healthy photoreceptors is a conserved phenomenon in mammalian species

“…Together with two recent studies describing possibly related structures in WT fish cones ( Giarmarco et al, 2020 ) and primate photoreceptors ( Hayes et al, 2021 ), these observations suggest that photoreceptor mitochondria have the ability to extrude some of their material to the extracellular space. Such a release of mitochondrial material has been observed in other cell types ( Simpson and Kling, 1968 ; Gasko and Danon, 1972 ), and is thought to take place under both normal and pathological conditions ( Lyamzaev et al, 2022 ). However, three questions regarding the mitochondria-associated structures in the photoreceptor inner segment remain to be addressed.…”

Research Progress on Mitochondrial Dysfunction in Diabetic Retinopathy

“…Regarding mitochondrial dynamic homeostasis, in addition to mitophagy, fusion and fission, recently, scholars have begun to focus on mitochondrial extrusion and intercellular transfer in many fields such as stroke, cardiovascular disease, and cancer [ 206 ]. On one hand, damaged or senescent mitochondria can be extruded from cells to maintain cellular homeostasis and prevent apoptosis.…”