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

Abstract

Background: 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.