RESUMEN
Mitochondria function as an integrated network that moves along the microtubules within cells and changes the morphology through membrane fusion and fission events. Mitofusin (MFN) mediates membrane tethering and subsequent fusion of the mitochondrial outer membrane. Understanding the regulatory mechanisms of MFN function is critical to tackling the pathology related to mitochondrial network imbalance. Here, we reveal a novel inhibitory mechanism of MFN-mediated fusion by mitochondrial Rho GTPase (Miro1) in response to elevated mitochondrial Ca2+ concentration ([Ca2+ ]m ). We showed that elevated [Ca2+ ]m prevents the fusion between mitochondria forming the outer membrane tether by ectopically expressing MFN. Lowering [Ca2+ ]m by treating cells with an inhibitor of mitochondrial calcium uniporter or knocking down Miro1/2 induces more fused networks. Miro1 interacts with MFN as supported by co-immunoprecipitation and protein association identified by proximity labeling proteomics. It suggests that Miro1 functions as a Ca2+ -sensor and inhibits MFN function at elevated [Ca2+ ]m. Miro1 EF-hand mutant has a compromised inhibitory effect, which reiterates Ca2+ -modulated regulation. Dysregulated Ca2+ -handling and mitochondrial network imbalance are highly relevant in the pathology of cancers, cardiovascular, and neurodegenerative diseases. Miro1 functions as a coordinated Ca2+ -responder by pausing mitochondrial transport while reducing network fusion and cooperating with Drp1-mediated fission. It likely prevents the detrimental effect of Ca2+m overload and facilitates mitophagy. Our finding reveals a novel regulation of mitochondrial network dynamics responding to [Ca2+ ]m through the interplay of Miro1 and MFN. Modulation of Miro1 and MFN interaction is a potential intervention to promote network homeostasis.
Asunto(s)
Calcio/metabolismo , GTP Fosfohidrolasas/metabolismo , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Proteínas Mitocondriales/metabolismo , Proteínas de Unión al GTP rho/metabolismo , GTP Fosfohidrolasas/genética , Células HEK293 , Humanos , Mitocondrias/genética , Proteínas de Transporte de Membrana Mitocondrial/genética , Proteínas Mitocondriales/genética , Proteínas de Unión al GTP rho/genéticaRESUMEN
Despite ongoing experiential change, neural activity maintains remarkable stability. Although this is thought to be mediated by homeostatic plasticity, what aspect of neural activity is conserved and how the flexibility necessary for learning and memory is maintained is not fully understood. Experimental studies suggest that there exists network-centered, in addition to the well-studied neuron-centered, control. Here we computationally study such a potential mechanism: input-dependent inhibitory plasticity (IDIP). In a hippocampal model, we show that IDIP can explain the emergence of active and silent place cells as well as remapping following silencing of active place cells. Furthermore, we show that IDIP can also stabilize recurrent dynamics while preserving firing rate heterogeneity and stimulus representation, as well as persistent activity after memory encoding. Hence, the establishment of global network balance with IDIP has diverse functional implications and may be able to explain experimental phenomena across different brain areas.