Mitochondrial Membrane Potential‐dependent Endoplasmic Reticulum Fragmentation is an Important Step in Neuritic Degeneration

SummaryBackground Neuritic degeneration is an important early pathological step in neurodegeneration. Aim The purpose of this study was to explore the mechanisms connecting neuritic degeneration to the functional and morphological remodeling of endoplasmic reticulum (ER) and mitochondria. Methods Here, we set up neuritic degeneration models by neurite cutting-induced neural degeneration in human-induced pluripotent stem cell-derived neurons. Results We found that neuritic ER becomes fragmented and forms complexes with mitochondria, which induces IP3R-dependent mitochondrial Ca2+ elevation and dysfunction during neuritic degeneration. Furthermore, mitochondrial membrane potential is required for ER fragmentation and mitochondrial Ca2+ elevation during neuritic degeneration. Mechanically, tightening of the ER–mitochondria associations by expression of a short “synthetic linker” and ER Ca2+ releasing together could promote mitochondrial Ca2+ elevation, dysfunction, and reactive oxygen species generation. Conclusion Our study reveals a dynamic remodeling of the ER–mitochondria interface underlying neuritic degeneration.