Increased ER-mitochondria tethering promotes axon regeneration.

Abstract

Translocation of the endoplasmic reticulum (ER) and mitochondria to the site of axon injury has been shown to facilitate axonal regeneration; however, the existence and physiological importance of ER-mitochondria tethering in the injured axons are unknown. Here, we show that a protein linking ER to mitochondria, the glucose regulated protein 75 (Grp75), is locally translated at axon injury site following axotomy, and that overexpression of Grp75 in primary neurons increases ER-mitochondria tethering to promote regrowth of injured axons. We find that increased ER-mitochondria tethering elevates mitochondrial Ca²⁺ and enhances ATP generation, thereby promoting regrowth of injured axons. Furthermore, intrathecal delivery of lentiviral vector encoding <i>Grp75</i> to an animal with sciatic nerve crush injury enhances axonal regeneration and functional recovery. Together, our findings suggest that increased ER-mitochondria tethering at axonal injury sites may provide a therapeutic strategy for axon regeneration.