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

Significance Organelles engage in heterotypic interactions crucial for metabolic and signaling cascades. The best-studied case of this heterotypic interaction is that between the mitochondria and endoplasmic reticulum (ER), crucial for transfer of lipids and especially Ca 2+ between the two organelles. The original discovery that the mitochondria-shaping protein Mitofusin 2 (Mfn2) physically tethers the ER to mitochondria was recently challenged. Here, electron microscopy and fluorescent probes of organelle proximity provide definitive evidence that constitutive or acute Mfn2 ablation increases the distance between the ER and mitochondria. Functionally, this process reduces mitochondrial Ca 2+ uptake without altering the mitochondrial Ca 2+ uniporter complex in multiple tissues. Thus, the discoveries of the role of ER–mitochondria juxtaposition in cell biology based on Mfn2 as a tool remain unchallenged.