Fig. 8.

Mechanisms of human OL lethal injury. In the absence of glucose uptake, glycolysis, the main source of ATP in hOL, is reduced. As ATP is necessary for the transport and fusion of autophagosomes and lysosomes, autophagy is impaired. Autophagy blockage results in process disruption in OLs, indicating that this mechanism is important for the structural integrity of the cell. Reduction in ATP levels also causes a decrease in the activity of ATP-dependent Ca²⁺ pumps, like plasma membrane calcium ATPase (PMCA), and the Na⁺K⁺ATPase, leading to an increase in cytosolic Ca²⁺ and Na⁺. The raise in intracellular Na⁺ increases the activity of Na⁺-Ca²⁺ exchangers, what causes an additional influx of Ca²⁺. High levels of Ca²⁺ activate Ca²⁺-dependent proteases as calpain, which cleave spectrin, an essential component for the integrity of the cytoskeleton. These mechanisms initially contribute to loss of hOL processes (sub-lethal injury) and subsequently to cell death. Figure created using Biorender.