Mfn2 localization in the ER is necessary for its bioenergetic function and neuritic development

Mfn2 is a mitochondrial fusion protein with bioenergetic functionsimplicated in the pathophysiology of neuronal and metabolicdisorders. Understanding the bioenergetic mechanism of Mfn2may aid in designing therapeutic approaches for these disorders.Here we show using endoplasmic reticulum (ER) or mitochondria-targeted Mfn2 that Mfn2 stimulation of the mitochondrial meta-bolism requires its localization in the ER, which is independent ofits fusion function. ER-located Mfn2 interacts with mitochondrialMfn1/2 to tether the ER and mitochondria together, allowing Ca2+transfer from the ER to mitochondria to enhance mitochondrialbioenergetics. The physiological relevance of these findings isshown during neurite outgrowth, when there is an increase inMfn2-dependent ER-mitochondria contact that is necessary forcorrect neuronal arbor growth. Reduced neuritic growth in Mfn2KO neurons is recovered by the expression of ER-targeted Mfn2 oran artificial ER-mitochondria tether, indicating that manipulationof ER-mitochondria contacts could be used to treat pathologicconditions involving Mfn2.