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. 2017 Nov;27(11):787-799.
doi: 10.1016/j.tcb.2017.08.009. Epub 2017 Sep 19.

Mitochondrial Nanotunnels

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Mitochondrial Nanotunnels

Amy E Vincent et al. Trends Cell Biol. .
Free PMC article


Insight into the regulation of complex physiological systems emerges from understanding how biological units communicate with each other. Recent findings show that mitochondria communicate at a distance with each other via nanotunnels, thin double-membrane protrusions that connect the matrices of non-adjacent mitochondria. Emerging evidence suggest that mitochondrial nanotunnels are generated by immobilized mitochondria and transport proteins. This review integrates data from the evolutionarily conserved structure and function of intercellular projections in bacteria with recent developments in mitochondrial imaging that permit nanotunnel visualization in eukaryotes. Cell type-specificity, timescales, and the selective size-based diffusion of biomolecules along nanotunnels are also discussed. The joining of individual mitochondria into dynamic networks of communicating organelles via nanotunnels and other mechanisms has major implications for organelle and cellular behaviors.

Keywords: communication; membrane dynamics; mitochondrion; nanotunnel; signaling.


Figure 1
Figure 1. Specialized Membrane-Based Tubular Structures Enable Cell–Cell and Mitochondria–Mitochondria Information Transfer
(A) Mammalian cell–cell exchange of organelles, vesicles, and soluble molecules occurs through cytonemes, nanotubes, and microtubules. (B) Within cells, mitochondria form similar tubular structures with contiguous outer and inner mitochondria membranes, and a continuous matrix space allowing the selective diffusion of specific molecular components. (C) Schematic of the nanotunnel junction, or ‘hillock’, showing the continuity of mitochondrial compartments. Nucleoid drawn to scale, see also Figure 2. (D) (Left) Scanning EM of intercellular nanotubes connecting PY79 bacteria [19]. (Center) Transmission EM of a tubular stromule extending from a chloroplast in a mesophyll cell of Arabidopsis thaliana [53]. (Right) Differential interference contrast (DIC) imaging of human HEK293 cells with cell–cell membrane protrusions. Abbreviations: EM, electron microscopy; IMM, inner mitochondrial membrane; mtDNA, mitochondrial DNA; OMM, outer mitochondrial membrane.
Figure 2
Figure 2. Anatomy of Mitochondrial Nanotunnels
(A) Four mitochondria connected by three nanotunnels (arrows) in human skeletal muscle. (B) A mitochondrion with a nanotunnel running adjacent to the nuclear envelope (yellow) in human skeletal muscle. The high magnification inset shows the nanotunnel double membrane with an internal lumen devoid of cristae. (C) Elongated tubular mitochondrion with variable diameter harboring cristae and a localized mitochondrial constriction with concave membrane curvature consistent with mitochondrial fission. (D) Mitochondria undergoing membrane constriction. Structures in (C,D) are not nanotunnels. (E) Hypothetical model of mitochondrial nanotunnels arising from immobilized mitochondria through the action of motor proteins. (Top) A free mitochondrion pulled by kinesin along a microtubule. (Bottom) A mitochondrion immobilized by anchoring proteins but pulled by the same kinesin protein, resulting in the production of a free nanotunnel. See text for discussion. (F) Human mitochondrial nanotunnel drawn to scale with a proton, GFP, and an mtDNA nucleoid [42]. (G) 3D reconstructions of free mitochondrial nanotunnels in human skeletal muscle showing blunt-end protrusions consistent with an autonomous mode of nanotunnel growth. The nanotunnel growth cones are shown with arrowheads.
Figure 3
Figure 3. Life Cycle of Mitochondrial Nanotunnels
This model proposes that initial nanotunnel sprouting starts with a membrane protrusion from a donor mitochondrion (step 1), subsequently elongating into a free nanotunnel (2). Nanotunnels then either contact a recipient mitochondrion for subsequent fusion (3A), stabilize, and further extend towards a signaling molecule (3B), or retract (3C) and resolve (3D). Fusion of mitochondrial nanotunnels with a recipient mitochondrion (4) leads to connecting nanotunnels, which can expand to accommodate cristae and generate tubular mitochondria (5). Incomplete mitochondrial fission of mitochondrial tubules may generate anatomically similar structures to nanotunnels.
Figure I
Figure I. Live-Cell Imaging and 3D EM Imaging of Mitochondrial Nanotunnels
(A) Dynamic mitochondrial nanotunnels in a freshly isolated adult ventricular cardiomyocytes (AVCM) expressing mito-targeted photoactivatable GFP (mtPA-GFP). Timelapse confocal imaging with time since photoconversion. (1) Early protrusion emerging from a globular mitochondrion. (2,3) Thin mitochondrial protrusions, likely representing free mitochondrial nanotunnels, emerging and retracting from a donor mitochondrion. Note that image contrast is enhanced (and mitochondria overexposed) to enable visualization of nanotunnels. (B) mtPA-GFP live-cell timelapse confocal imaging of an AVCM showing the relatively slow exchange kinetics of PA-GFP to a receiver mitochondrion over ~40 s. The bottom plot represents the diffusion kinetics of the receiver mitochondrion: an increase of mtPA-GFP fluorescence and a simultaneous decrease of mtDsRed (mitochondrial matrix targeted Discosoma sp. red fluorescent protein) that replenished the PA-GFP donor organelle which suffered photobleaching upon GFP photoconversion (adapted from [28]). (C) Serial block-face scanning electron microscopy (SBF-SEM; Gatan 3 view) showing pseudocolored mitochondrial nanotunnels running through the image plane in longitudinal and (D) transverse orientations. A 3D surface reconstruction of nanotunnels is shown below. In (D) every fourth image is shown where the actual section thickness is 30 nm.<stream name=“fig_1365_gr1b2” position=“4” desc=“1”/

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