Mitochondria Know No Boundaries: Mechanisms and Functions of Intercellular Mitochondrial Transfer

Abstract

Mitochondria regulate multiple cell processes, including calcium signaling, apoptosis and cell metabolism. Mitochondria contain their own circular genome encoding selected subunits of the oxidative phosphorylation complexes. Recent findings reveal that, in addition to being maternally inherited, mitochondria can traverse cell boundaries and thus be horizontally transferred between cells. Although, the physiological relevance of this phenomenon is still under debate, mitochondria uptake rescues mitochondrial respiration defects in recipient cells and regulates signaling, proliferation or chemotherapy resistance in vitro and in vivo. In this review, we outline the pathophysiological consequences of horizontal mitochondrial transfer and offer a perspective on the cellular and molecular mechanisms mediating their intercellular transmission, including tunneling nanotubes, extracellular vesicles, cellular fusion, and GAP junctions. The physiological relevance of mitochondrial transfer and the potential therapeutic application of this exchange for treating mitochondrial-related diseases are discussed.

Keywords: DAMPs; communication; exosomes; extracellular vesicles; horizontal genetic transfer; inflammation; mitochondrial diseases; tunneling nanotubes.

Figure 1

Cellular mechanisms of intercellular mitochondrial transfer. (A) Tunneling nanotubes (TNT) are long ultrathin structures with diameters ranging from 50 to 200 nm and a length that allow organelle transfer between two spatially separated cells. TNTs contain cytoskeletal elements such as actin and microtubules depending on the cell type. Myosin is a fundamental protein for the organelle transfer, a process where high rates of ATP consumption are needed. Rho GTPases play an important role in organelle transfer through TNT. Miro1 and microtubules have been involved in the transfer of mitochondria upon injury (Ahmad et al., 2014). (B) Cell fusion is a process, in which two independent cells fuse their membranes and share organelles and cytosolic compounds, however nuclei remain intact. Cell fusion can be transitory and therefore lose their integrity transiently or complete, where cells will share cytoplasm continuously, for example in muscle cells. It has been shown that after myocardial infarct stem cell therapy can lead to a better recovery and it is proved that partial or total fusion events can happen between cardiomyocytes and stem cells (Oh et al., 2003). By this mechanism mitochondrial respiration can be restored and this could be an indicative marker for cardiac regeneration after infarct. (C) GAP junctions. LPS treatment increases connexin 43 expression in alveolar cells. Connexins facilitate the attachment of BMSC to the alveolar epithelial cells, and produce vesicles and nanotubes to share mitochondria with the damaged cells protecting against acute lung injury (Islam et al., 2012).

Figure 2

Loading of mitochondrial components in Extracellular Vesicles. Exosomes are small vesicles from 50 to 150 nm with an endocytic origin. The inward budding of late endosomes or multivesicular bodies (MVB) forms intraluminal vesicles that are released into the extracellular environment as exosomes through fusion of the MVB with the plasma membrane. Microvesicles, also called ectosomes, shed directly from plasma membrane and are very heterogeneous in size and composition. Apoptotic bodies are larger than 1 μm and are released by apoptotic cells that shed parts of their cytoplasm and organelles surrounded by plasma membrane (Mittelbrunn and Sánchez-Madrid, 2012). Extracellular vesicles can contain mitochondrial fragments which include mitochondrial proteins and mtDNA (depicted in yellow and orange). Bigger particles can be loaded with full functional mitochondria (Phinney et al., 2015).