Model represents both GSK3β- and PKA-mediated Drp1 phosphorylation induction of mitochondrial elongation which subsequently causes acquired resistance to H2O2-induced apoptosis rather than inducing autophagy.
Mitochondria dynamics regulate the GTPase hydrolysis activity of proteins (Drp1, Opa1, Mfn1 and 2) resulting in mitochondrial fission or fusion. In this model, two Drp1 phosphorylation sites could serve a regulatory function, including phosphorylation by PKA/AKAP1 on Ser637 [39] or by GSK3β on Ser693 (as shown in this study), leading to diminished mitochondrial fission resulting in mitochondrial elongation. GSK3β might be recruited to mitochondria through AKAP220 and be dephosphorylated by PP1, 2, and 3 [40]. Such mitochondrial morphological changes could also result in cell fate determination. Mitochondrial fission is involved in the initiation of apoptosis, whereas mitochondrial fusion may induce autophagy. Both phosphorylation events occurring at S637 and S693 cause elongated mitochondrial morphology and lead to acquired resistance to H2O2-induced mitochondrial fragmentation and ensuing apoptosis via down-regulating cytochrome c release, capase-3, -7 and PARP activations rather than inducing autophagy.
