MFN2はミトコンドリアをほかの細胞小器官に融合させるときに機能する蛋白です。融合することによってミトコンドリアと相手方器官が正常な機能を果たせます。

多くの神経変性疾患で異常をしめしています

例えば、MFN2がちゃんと機能しているT細胞は癌細胞の増殖を抑えたりします。＞＞Metabolic fitness of T cells is essential for their vitality, which is largely dependent on the behavior of the mitochondria. The nature of mitochondrial behavior in tumor-infiltrating T cells remains poorly understood.

In this study, we show that mitofusin-2 (MFN2) expression is positively correlated with the prognosis of multiple cancers. Genetic ablation of Mfn2 in CD8⁺ T cells dampens mitochondrial metabolism and function and promotes tumor progression.

In tumor-infiltrating CD8⁺ T cells, MFN2 enhances mitochondria-endoplasmic reticulum (ER) contact by interacting with ER-embedded Ca²⁺-ATPase SERCA2, facilitating the mitochondrial Ca²⁺ influx required for efficient mitochondrial metabolism. MFN2 stimulates the ER Ca²⁺ retrieval activity of SERCA2, thereby preventing excessive mitochondrial Ca²⁺ accumulation and apoptosis. Elevating mitochondria-ER contact by increasing MFN2 in CD8⁺ T cells improves the efficacy of cancer immunotherapy.

Thus, we reveal a tethering-and-buffering mechanism of organelle cross-talk that regulates the metabolic fitness of tumor-infiltrating CD8⁺ T cells and highlights the therapeutic potential of enhancing MFN2 expression to optimize T cell function.　細胞機能を大いに発揮するためにはミトコンドリアと小胞体の同期/テザリンングが必要でそれを担保するのがＭＦＮ２であるといことです

この論文ではMFN2は細胞機能をちゃんと作動させるために行き過ぎの細胞小器官の融合を抑えていると主張しています。＞＞The organization and mutual interactions between endoplasmic reticulum (ER) and mitochondria modulate key aspects of cell pathophysiology.

Several proteins have been suggested to be involved in keeping ER and mitochondria at a correct distance.

Among them, in mammalian cells, mitofusin 2 (Mfn2), located on both the outer mitochondrial membrane and the ER surface, has been proposed to be a physical tether between the two organelles, forming homotypic interactions and heterocomplexes with its homolog Mfn1.

Recently, this widely accepted model has been challenged using quantitative EM analysis.

Using a multiplicity of morphological, biochemical, functional, and genetic approaches, we demonstrate that Mfn2 ablation increases the structural and functional ER-mitochondria coupling.

In particular, we show that in different cell types Mfn2 ablation or silencing increases the close contacts between the two organelles and strengthens the efficacy of inositol trisphosphate (IP3)-induced Ca(2+) transfer from the ER to mitochondria, sensitizing cells to a mitochondrial Ca(2+) overload-dependent death.

We also show that the previously reported discrepancy between electron and fluorescence microscopy data on ER-mitochondria proximity in Mfn2-ablated cells is only apparent.

By using a different type of morphological analysis of fluorescent images that takes into account (and corrects for) the gross modifications in mitochondrial shape resulting from Mfn2 ablation, we demonstrate that an increased proximity between the organelles is also observed by confocal microscopy when Mfn2 levels are reduced.

Based on these results, we propose a new model for ER-mitochondria juxtaposition in which Mfn2 works as a tethering antagonist preventing an excessive, potentially toxic, proximity between the two organelles.

The privileged interrelationship between mitochondria and the endoplasmic reticulum (ER) plays a key role in a variety of physiological functions, from lipid metabolism to Ca²⁺ signalling, and its modulation influences apoptotic susceptibility, mitophagy, and cellular bioenergetics.

Among the several proteins known to influence ER–mitochondria interactions, mitofusin 2 (Mfn2) has been proposed to form a physical tether.

In this study, we demonstrate that Mfn2 instead works as an ER–mitochondria tethering antagonist preventing an excessive, potentially toxic, proximity between the two organelles.

Cells in which Mfn2 is ablated or reduced have an increased number of ER–mitochondria close contacts, potentiated Ca²⁺ transfer between the two organelles, and greater sensitivity to cell-death stimuli that implies mitochondria Ca²⁺ overload toxicity.