Figure 8.

The close ultrastructural relationship between the myocardial mitochondria (Mt) and the endoplasmic reticulum (ER) in the hypertensive 7-week-old male Ren2 model with insulin resistance and impaired glucose tolerance. Panel A demonstrates that cardiomyocyte Mt are actually in very close contact with the ER (arrows), which would enable considerable crosstalk in the white dashed boxed-in region. Importantly, note the normal electron-dense Mt in the far left-hand side of this image and insert (a) and compare them to the aberrant Mt (aMt) (electron hyperlucent Mt with loss of crista) in panel B. Panel B depicts a higher magnified exploded view from the dashed boxed-in region of panel A. Note the extremely electron-dense membranes of the endoplasmic reticulum (ER) and how the outer membranes of the ER appear to be touching and possibly communicating with the outer membranes of the aberrant Mt (aMt) termed mitochondria-associated membrane(s) or (MAMs). Further, note that the aMt (outlined in red) are in close proximity and apposition with the ER membranes (pseudo-colored blue). This indicates, at the very least, an ultrastructural potential for ER-Mt crosstalk due to MAMs. There is close proximity of less than 100 nm to the actual contact between the outer membranes of the aMt and the ER. This close apposition and touching of the MAMs may allow for considerable crosstalk between the ER and Mt and thus allow for calcium and reactive oxygen species transfer, which may increase ER stress when there is Mt dysfunction due to aMt since the ER utilizes ATP from the Mt. Importantly, impaired Mt fission and mitophagy machinery in concert with ER stress may result in cellular apoptosis. This close apposition/touching allows MAMs to be responsible for (1) calcium buffering; (2) Mt fission; (3) phospholipid exchange. Importantly, the longer these aberrant Mt are not ‘taken-out’ or removed by mitophagy the greater the possibility for reactive oxygen species (mt ROS) and calcium to leak and cause further generation of reactive oxygen, nitrogen, and sulfur species to active the reactive species RONSS interactome and cardiomyocyte dysfunction and Mt leakage of cytochrome c to induce myocardial cellular apoptosis. While this image is from the Ren2 hypertensive myocardium experiment [27], this close association between the ER and aMt is known to be present in other organs in multiple different disease states. Original magnification = ×10,000; scale bars = 500 nm. DRP1 = dynamin-related protein 1 necessary for Mt fission.