Critical reappraisal confirms that Mitofusin 2 is an endoplasmic reticulum-mitochondria tether.

Abstract

The discovery of the multiple roles of mitochondria-endoplasmic reticulum (ER) juxtaposition in cell biology often relied upon the exploitation of Mitofusin (Mfn) 2 as an ER-mitochondria tether. However, this established Mfn2 function was recently questioned, calling for a critical re-evaluation of Mfn2's role in ER-mitochondria cross-talk. Electron microscopy and fluorescence-based probes of organelle proximity confirmed that ER-mitochondria juxtaposition was reduced by constitutive or acute Mfn2 deletion. Functionally, mitochondrial uptake of Ca²⁺ released from the ER was reduced following acute Mfn2 ablation, as well as in Mfn2^-/- cells overexpressing the mitochondrial calcium uniporter. Mitochondrial Ca²⁺ uptake rate and extent were normal in isolated Mfn2^-/- liver mitochondria, consistent with the finding that acute or chronic Mfn2 ablation or overexpression did not alter mitochondrial calcium uniporter complex component levels. Hence, Mfn2 stands as a bona fide ER-mitochondria tether whose ablation decreases interorganellar juxtaposition and communication.