Chronic mitochondrial stress is associated with major neurodegenerative diseases; and thus, the recovery of those mitochondria constitutes a critical step of energy maintenance in early stages of neurodegeneration. Our recent study provides the first lines of evidence showing that the MUL1-MFN2 pathway acts as an early checkpoint to maintain mitochondrial integrity by regulating mitochondrial morphology and interplay with the endoplasmic reticulum (ER). This mechanism ensures that degradation through mitophagy is restrained in neurons under early stress conditions. MUL1 deficiency increases MFN2 activity, triggering the first phase of mitochondrial hyperfusion and acting as an antagonist of ER-mitochondria (ER-Mito) tethering. Reduced ER-Mito interplay enhances the cytoplasmic Ca2+ load that induces the DNM1L/Drp1-dependent second phase of mitochondrial fragmentation and mitophagy. Our study provides new mechanistic insights into neuronal mitochondrial maintenance under stress conditions. Identifying this pathway is particularly relevant because chronic mitochondrial dysfunction and altered ER-Mito contacts have been reported in major neurodegenerative diseases.

中文翻译：

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保护应激线粒体：揭示 MUL1 在抑制神经元线粒体自噬中的作用。


慢性线粒体应激与主要的神经退行性疾病有关；因此，这些线粒体的恢复是神经变性早期阶段能量维持的关键步骤。我们最近的研究提供了第一批证据，表明 MUL1-MFN2 通路作为早期检查点，通过调节线粒体形态和与内质网 (ER) 的相互作用来维持线粒体完整性。这种机制确保在早期应激条件下神经元中通过线粒体自噬引起的降解受到抑制。 MUL1 缺乏会增加 MFN2 活性，引发线粒体过度融合的第一阶段，并充当 ER 线粒体 (ER-Mito) 束缚的拮抗剂。 ER-Mito 相互作用减少会增强细胞质 Ca2+ 负荷，从而诱导 DNM1L/Drp1 依赖性线粒体断裂和线粒体自噬的第二阶段。我们的研究为应激条件下神经元线粒体的维持提供了新的机制见解。识别该通路尤其重要，因为在主要的神经退行性疾病中已有慢性线粒体功能障碍和 ER-Mito 接触改变的报道。