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

Mfn2 is a mitochondrial fusion protein with bioenergetic functions implicated in the pathophysiology of neuronal and metabolic disorders. Understanding the bioenergetic mechanism of Mfn2 may 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 metabolism requires its localization in the ER, which is independent of its fusion function. ER-located Mfn2 interacts with mitochondrial Mfn1/2 to tether the ER and mitochondria together, allowing Ca 2+ transfer from the ER to mitochondria to enhance mitochondrial bioenergetics. The physiological relevance of these findings is shown during neurite outgrowth, when there is an increase in Mfn2-dependent ER-mitochondria contact that is necessary for correct neuronal arbor growth. Reduced neuritic growth in Mfn2 KO neurons is recovered by the expression of ER-targeted Mfn2 or an artificial ER-mitochondria tether, indicating that manipulation of ER-mitochondria contacts could be used to treat pathologic conditions involving Mfn2. Synopsis The bioenergetic role of Mfn2 relies on its localization in the ER. Mfn2 localization to mitochondria is dispensable in the presence of mitochondrial Mfn1, which tethers ER and mitochondria, and facilitates Ca 2+ transfer. Mfn2 regulates metabolism independent of its mitochondrial fusion function. Mfn2 localization in the ER is necessary to maintain mitochondrial bioenergetics. Mfn2 is an ER-mitochondria tether whose depletion alters ER and mitochondrial Ca 2+ levels. Restoration of ER-mitochondria contacts corrects altered Ca 2+ homeostasis and bioenergetics defects in Mfn2 KO cells. Mfn2-mediated ER-mitochondria tethering is necessary for proper neurite outgrowth. Graphical Abstract The bioenergetic role of Mfn2 relies on its localization in the ER. Mfn2 localization to mitochondria is dispensable in the presence of mitochondrial Mfn1, which tethers ER and mitochondria, and facilitates Ca 2+ transfer.