Fig. 9: Illustration of mitochondrial dynamics during degeneration and recovery of neuronal PC12 cells.

EtOH treatment for 3 h already induced cellular changes and damage such as reactive oxygen species generation, elevation of intracellular Ca²⁺, phosphatidylserine exposure, nuclear shrinkage, DNA damage, mitochondrial fragmentation and mitochondrial membrane potential loss, and retraction of neurites [17]. These phenomena are often associated with regulated cell death. Importantly, after removing ethanol and further culturing the dying cells in fresh culture medium, cells recovered from all these cellular injuries and generated new neurites. In the phase of EtOH induced cellular degeneration, the expression of phospho-Drp1^Ser616 and S-OPA1 that are related to mitochondrial fission were increased. The expression of MFN1, MFN2, L-OPA1, and PGC-1α that are related to mitochondrial fusion and biogenesis were decreased. Meanwhile, autophagy was activated. In the phase of cellular recovery after removing EtOH, mitochondrial fusion and biogenesis increased and recovered. Inhibiting mitochondrial biogenesis by PGC-1α inhibitor SR-18292 showed remarkable inhibition of not only recovery of mitochondria, but also of neurite regeneration and cell survival. These results indicate that PGC-1α mediated mitochondrial biogenesis may be a potential target for rescuing dying/injured neurons in neurodegenerative diseases.