Mohylyak Iryna, Andriatsilavo Maheva, Bengochea Mercedes, Pascual-Caro Carlos, Asfogo Noemi, Fonseca-Topp Sara, Danda Natasha, Cassar Marlene, Marie Corentine, Atak Zeynep Kalender, De Waegeneer Maxime, Aerts Stein, Corti Olga, de Juan-Sanz Jaime, Hassan Bassem A
Institut du Cerveau-Paris Brain Institute (ICM), Sorbonne Université, Inserm, CNRS, Hôpital Pitié-Salpêtrière, Paris, France.
Laboratory of Computational Biology, Center for Brain and Disease Research - VIB-KU Leuven, Leuven, Belgium.
Nat Commun. 2025 Sep 1;16(1):8173. doi: 10.1038/s41467-025-62908-2.
Synaptic connectivity during development is known to require rapid local regulation of axonal organelles. Whether this fundamental and conserved aspect of neuronal cell biology is orchestrated by a dedicated developmental program is unknown. We hypothesized that developmental transcription factors regulate critical parameters of organelle structure and function which contribute to circuit wiring. We combined cell type-specific transcriptomics with a genetic screen to discover such factors. We identified Drosophila CG7101, which we rename mitochondrial integrity regulator of neuronal architecture (Mirana), as a temporal developmental regulator of neuronal mitochondrial quality control genes, including Pink1. Remarkably, a brief developmental downregulation of either Mirana or Pink1 suffices to cause long-lasting changes in mitochondrial morphology and abrogates neuronal connectivity which can be rescued by Pink1 expression. We show that Mirana has functional homology to the mammalian transcription factor TZAP whose loss leads to changes in mitochondrial function and reduced neurotransmitter release in hippocampal neurons. Our findings establish temporal developmental transcriptional regulation of mitochondrial morphology as a prerequisite for the priming and maintenance of activity-dependent synaptic connectivity.
已知发育过程中的突触连接需要对轴突细胞器进行快速的局部调节。这种神经元细胞生物学的基本且保守的方面是否由专门的发育程序精心安排尚不清楚。我们推测发育转录因子调节细胞器结构和功能的关键参数，这些参数有助于神经回路的布线。我们将细胞类型特异性转录组学与基因筛选相结合以发现此类因子。我们鉴定出果蝇CG7101，我们将其重新命名为神经元结构线粒体完整性调节因子（Mirana），作为包括Pink1在内的神经元线粒体质量控制基因的时间发育调节因子。值得注意的是，短暂下调Mirana或Pink1的发育水平足以导致线粒体形态发生持久变化，并消除神经元连接，而Pink1的表达可以挽救这种连接。我们表明Mirana与哺乳动物转录因子TZAP具有功能同源性，TZAP的缺失会导致线粒体功能改变以及海马神经元中神经递质释放减少。我们的研究结果表明，线粒体形态的时间发育转录调节是启动和维持依赖活动的突触连接的先决条件。
