Biophysics & Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India.
Homi Bhabha National Institute, Mumbai, Maharashtra, India.
Biol Cell. 2022 Nov;114(11):309-319. doi: 10.1111/boc.202100098. Epub 2022 Aug 17.
Mitofusin2 (MFN2), an important molecular player that regulates mitochondrial fusion, also helps maintain the inter-organellar contact sites, referred as mitochondria associated membranes (MAMs) that exist between the ER and mitochondria. The study deals with a mutant of MFN2, R364W-MFN2, linked with the neuropathy, Charcot Marie Tooth (CMT) disease. Previous studies show that this mutant promotes mitochondrial hyperfusion. Here, we try to decipher the role of R364W-MFN2 in affecting the ER mitochondrial associations at the MAM junctions and inter-organellar calcium signalling between the ER and the mitochondria.
Our results show that R364W-MFN2 altered ER-mitochondria association at the MAM junctions, predisposed mitochondria towards cellular stress with the mitochondria undergoing rapid fission upon induction of mild stress and perturbs inter-organellar calcium homeostasis.
The results indicate that R364W-MFN2 not only affects mitochondrial morphology and dynamics but also modulate its interaction with the ER and Ca signalling between the two organelles.
This study provides significant insight that presence of the R364W-MFN2 mutation makes cells susceptible towards stress, thus negatively affecting cellular health which altogether might culminate in the form of the CMT neuropathy.
线粒体融合相关蛋白 2（MFN2）是一种重要的分子调控因子，参与调控线粒体融合，同时也有助于维持内质网（ER）和线粒体之间的细胞器间接触位点，即线粒体相关膜（MAMs）。该研究涉及与神经病、Charcot-Marie-Tooth（CMT）疾病相关的 MFN2 突变体 R364W-MFN2。先前的研究表明，这种突变体促进线粒体过度融合。在这里，我们试图阐明 R364W-MFN2 在影响 MAM 连接处 ER 与线粒体关联以及 ER 和线粒体之间细胞器间钙信号传递中的作用。
我们的结果表明，R364W-MFN2 改变了 MAM 连接处的 ER-线粒体关联，使线粒体容易受到细胞应激的影响，在轻度应激诱导下，线粒体迅速发生裂变，并破坏细胞器间的钙稳态。
研究结果表明，R364W-MFN2 不仅影响线粒体的形态和动力学，还调节其与 ER 的相互作用以及两个细胞器之间的钙信号传递。
这项研究提供了重要的见解，即 R364W-MFN2 突变的存在使细胞易受应激影响，从而对细胞健康产生负面影响，这可能最终导致 CMT 神经病。
