Figure 7.

Autophagy regulation in control and KdVS cells. Schematic representation of autophagy regulating mechanisms. In control cells both, dephosphorylation of MTOR and increased ROS levels, induce autophagosome formation. Upon completion, autophagosomes induce negative feedback-loops. ATG gene expression is reduced through decreased H4K16ac levels, on the one hand. On the other hand, MTOR phosphorylation increases upon autophagosome accumulation to inhibit MTOR regulated autophagy, and subsequently reduces lysosomes. In KdVS cells prolonged oxidative stress induces autophagy, primarily MTOR independent. While H4K16ac is not reduced, enabling expression of ATG genes and continuous autophagosome formation, the accumulation of autophagosomes induces a reduction in MTOR activity, reducing lysosomal activity, and preventing autophagosomal clean-up. Aberrant feedback-loop activation in KdVS cells therefore causes an imbalance in oxidative stress versus MTOR activated autophagy reinforcing elevated autophagosome accumulation.