Mitofusin 2 tethers endoplasmic reticulum to mitochondria

Abstract

Juxtaposition between endoplasmic reticulum (ER) and mitochondria is a common structural feature, providing the physical basis for intercommunication during Ca(2+) signalling; yet, the molecular mechanisms controlling this interaction are unknown. Here we show that mitofusin 2, a mitochondrial dynamin-related protein mutated in the inherited motor neuropathy Charcot-Marie-Tooth type IIa, is enriched at the ER-mitochondria interface. Ablation or silencing of mitofusin 2 in mouse embryonic fibroblasts and HeLa cells disrupts ER morphology and loosens ER-mitochondria interactions, thereby reducing the efficiency of mitochondrial Ca(2+) uptake in response to stimuli that generate inositol-1,4,5-trisphosphate. An in vitro assay as well as genetic and biochemical evidences support a model in which mitofusin 2 on the ER bridges the two organelles by engaging in homotypic and heterotypic complexes with mitofusin 1 or 2 on the surface of mitochondria. Thus, mitofusin 2 tethers ER to mitochondria, a juxtaposition required for efficient mitochondrial Ca(2+) uptake.

ApoE4 upregulates the activity of mitochondria‐associated ER membranes

“…We therefore asked whether the ApoE4‐mediated increase in phospholipid synthesis could be abrogated in Mfn2 ‐KO cells. Similar to what we observed in the human fibroblasts 31, treatment of wild‐type MEFs with ApoE4 ACM resulted in an increase in PtdSer (~1.5 ± 0.3) and PtdEtn (~1.6 ± 0.2) production compared to ApoE3 ACM (Fig 1C). However, we found no such increase in either PtdSer (~1.0 ± 0.2) or PtdEtn (~0.9 ± 0.1) production in the Mfn2 ‐KO MEFs (Fig 1C), strongly suggesting that the ApoE4‐mediated effect on phospholipid metabolism was indeed the result of increased ER–mitochondrial communication.…”

“…Mfn2, in addition to its role in mitochondrial fusion, tethers ER to mitochondria 31; importantly, genetic ablation of Mfn2 reduces this connectivity 31. Consistent with this loss in interorganellar communication, we had previously established that PtdSer and PtdEtn production is reduced significantly in Mfn2 ‐KO MEFs 7.…”

Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

“…To assess apposition, we transfected control and PS‐DKO cells with markers of ER and mitochondria, and measured their colocalization (de Brito & Scorrano, 2008; Area‐Gomez et al , 2012) in the absence or presence of BI to prevent the generation of C99; remarkably, incubation with BI rescued the upregulation of ER–mitochondria apposition seen in mutant cells (Fig 3A and B).…”

Mfn2 is critical for brown adipose tissue thermogenic function

“…Mfn2 has been proposed to influence the interaction between mitochondria and other organelles, such as the endoplasmic reticulum (ER) (de Brito & Scorrano, 2008; Cosson et al , 2012; Filadi et al , 2015). In line with this, Mfn2 deficiency has been shown to trigger ER stress at least in liver, brain, and muscle (Sebastian et al , 2012; Schneeberger et al , 2013).…”

“…Many of these effects have been attributed to the ability of Mfn2 to mediate not only mitochondria–mitochondria contacts, but also to influence the interaction of mitochondria with other cellular membrane organelles. For example, Mfn2 has a critical role in the maintenance of mitochondria–endoplasmic reticulum (ER) interactions (de Brito & Scorrano, 2008; Cosson et al , 2012; Filadi et al , 2015), and ablation of Mfn2 triggered ER stress in virtually all models tested (Sebastian et al , 2012; Schneeberger et al , 2013). …”