Figure 19.

Emerging evidence may suggest a possibility for a bidirectional relationship between aberrant Mt (aMt) and the endothelial glycocalyx (ecGCx) dysfunction and/or loss in endothelial cells, including brain endothelial cell(s) (BECs) and possibly other organs in obesity, insulin resistance (IR), leptin resistance (LR), metabolic syndrome (MetS), and type 2 diabetes mellitus (T2DM). This figure illustrates that there may be a bidirectional relationship between aMt and dysfunction, attenuation, and/or loss (shedding) of the brain BECs ecGCx. Note that this illustration establishes the role of oxidant stress—reactive oxygen species (ROS) in BECs and specifically mitochondrial ROS (mtROS) (left-hand box). Further, it establishes the important role of the dysfunctional attenuated and/or loss of the ecGCx in the brain (center box). Next, it establishes that obesity, IR, LR, impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and overt T2DM are related to increased Mt fission, decreased mitophagy, and the accumulation of leaky aMt that leak mtROS (right-hand box). Further, this image depicts that these leaky aMt may be responsible for the attenuation and/or loss of the ecGCx (red-dashed arrows) and that, in turn, may result in the loss of the ecGCx that may contribute to an increase in aMt (black-dashed arrows). Importantly, mtROS superoxide or H₂O₂ could oxidize the essential tetrahydrobiopterin (BH4) cofactor that is absolutely essential for the eNOS enzyme to produce nitric oxide (NO) and result in eNOS uncoupling, which would ultimately result in decreased bioavailable NO. This bidirectional interaction could result in a vicious cycle, which could be interrupted by preventing the accumulation of aMt (improved mitophagy) or preventing the dysfunction, attenuation, and/or loss (shedding) of the ecGCx [38,59,60,61,62,63,64,65,66,67,68]. The asterisk signifies emphasis of complex III.