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. 2015 Feb 17;6:6259.
doi: 10.1038/ncomms7259.

Trans-mitochondrial Coordination of Cristae at Regulated Membrane Junctions

Free PMC article

Trans-mitochondrial Coordination of Cristae at Regulated Membrane Junctions

Martin Picard et al. Nat Commun. .
Free PMC article


Reminiscent of bacterial quorum sensing, mammalian mitochondria participate in inter-organelle communication. However, physical structures that enhance or enable interactions between mitochondria have not been defined. Here we report that adjacent mitochondria exhibit coordination of inner mitochondrial membrane cristae at inter-mitochondrial junctions (IMJs). These electron-dense structures are conserved across species, resistant to genetic disruption of cristae organization, dynamically modulated by mitochondrial bioenergetics, independent of known inter-mitochondrial tethering proteins mitofusins and rapidly induced by the stable rapprochement of organelles via inducible synthetic linker technology. At the associated junctions, the cristae of adjacent mitochondria form parallel arrays perpendicular to the IMJ, consistent with a role in electrochemical coupling. These IMJs and associated cristae arrays may provide the structural basis to enhance the propagation of intracellular bioenergetic and apoptotic waves through mitochondrial networks within cells.


Figure 1
Figure 1. Electron-dense inter-mitochondrial junctions (IMJs) link adjacent mitochondria in the heart.
(a) Electron micrograph of mouse cardiomyocytes showing mitochondria with electron-dense IMJs (red arrows) and non-electron-dense contacts (yellow double arrowheads). (b,b′) Higher magnification showing apposed outer mitochondrial membranes and increased membrane electron density. (c) Relative electron density of mitochondrial membrane structures (means±s.e.m., one-way analysis of variance with Dunnett’s multiple comparisons, n=20 per group). (d) Diagram of the relative electron density of IMJ across 20 IMJs. (e) IMJs are unique to mito–mito contacts (arrow) and do not form with the sarcoplasmic reticulum (yellow) here juxtaposed to the mitochondrial outer membrane. Cristae membranes forming junctions at IMJs are outlined with dotted lines (also in b′).
Figure 2
Figure 2. Mitochondrial cristae are more abundant and coordinate at IMJs.
(a,b) Three-dimensional tomographic reconstruction used to quantify cristae abundance at mito–mito (green) and mito–myofibrils (MF, blue) contacts. L, lipid droplet, (mean±s.e.m., paired T-test, n=510 cristae from four complete tomograms). (c,c′) Cardiomyocyte mitochondria with cristae exhibiting a high degree of trans-mitochondrial alignment. (d) Pairs of mitochondria analyzed for degree of cristae alignment at IMJs and non-electron-dense contacts (non-IMJ) showing preferential alignment at IMJs. (mean±s.e.m., χ2, n=83–151 pairs per group). (e) ‘Fingerprint’ electron micrograph of mouse heart cardiomyocyte mitochondria processed to outline cristae, illustrating representative events of mitochondrial alignment at electron-dense junction sites (IMJ, red arrow), and non-alignment at non-electron-dense contacts (non-IMJ, yellow arrow). (f) Quantification of incident angles between mitochondria joined by IMJ or non-IMJ. IMJ inter-mitochondrial cristae angles exhibit less variability and closer to exact orientation (angle of 0°) than non-IMJ. Med, median.
Figure 3
Figure 3. Preferred cristae orientation and organisation at IMJs.
Disruption of mitochondrial function and cristae architecture by Ant1 deletion and ND6 mutation does not eliminate IMJs (arrow) and trans-mitochondrial cristae alignment in the skeletal muscle (a) or the heart (b). See Supplementary Video 1 for animation of tomogram (b). (c) Orientation of cristae relative to the tangent of mito-mito contacts (IMJs and non-IMJ) quantified on electron micrographs. An incident angle of 0° indicates that cristae lie parallel to the site of contact, whereas an angle of 90° indicates perpendicular cristae orientation. (d) Frequency distribution of cristae angle in both IMJ and non-IMJ (P<0.01). Note the near-random distribution of cristae orientations at non-IMJs. Frequency distributions compared based on 99% confidence interval of the mean, n=302 IMJs and 166 non-IMJ contacts.
Figure 4
Figure 4. IMJs are physiologically regulated and do not require mitofusins.
(a) Proportion of mitochondrial IMJs in various cells and tissues. (b) IMJs and cristae alignment occur in cardiomyocytes from wild type (WT), (c) Mfn1 knochout (Mfn1KO), (d) Mfn2KO and (e) inducible Mfn1/Mfn2-double knockout (Mfn1/2DKO) mice.
Figure 5
Figure 5. Mito–mito linker induces IMJs and coordination of cristae.
(a,a′) Confocal imaging of RBL-2H3 cells transfected with mitochondria-targeted inducible linkers at 0 min and (b,b′) 30 min post-induction with rapamycin. (c,d) Electron micrographs from (c) non-induced and (d) 30 min post-induction of mitochondrial linkage, (e) showing increased electron density selectively at site of contacts (means±s.e.m., paired T-test, n=20 per group). (f,g) Quantification of cristae abundance at linker-induced contact sites compared with no contact mitochondrial surfaces (means±s.e.m., paired T-test, n=14 per group). (h) Theoretical model whereby cristae organization and density are regulated at IMJs, possibly enabling the equilibration of the membrane potential across physically tethered organelles. **P<0.01, ***P<0.001.

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