Abstract
Functional neuronal circuits require a constant remodeling of their network composed of highly interconnected neurons. The plasticity of synapses and the shaping of elaborated dendritic branches are energy demanding and therefore depend on an efficient mitochondrial oxidative phosphorylation (OXPHOS). The spatial and functional regulations of dendritic patterning occur also after cell fate specification; however, the molecular mechanisms underlying this complex process remain elusive. Here, we exploit the changes in dendritic architecture in highly branched neurons as a result of aberrant mitochondrial activity. In sensory neurons of Caenorhabditis elegans, genetic manipulations of mitochondrial complex I subunits cause an unexpected outgrowth of dendritic arbors and ectopic structures. The increased number of dendritic branches is coordinated through a specific signaling cascade rather than as a simple consequence of oxidative stress. On the basis of genetic and pharmacological evidence, we show that OXPHOS deficiency promotes branching through the activation of the AMP-activated protein kinase AMPK and the downstream target phosphoinositide 3-kinase PI3K. Taken together, our findings describe a well-defined signaling pathway that regulates dendritic outgrowth in conditions of compromised OXPHOS and the resulting AMPK activation.
Highlights
Given their essential role in cellular metabolism, genetically inherited mutations as well as off-target effects of chemical compounds that disturb mitochondrial functions can seriously impinge healthy lifespan and inevitably lead to severe syndromes or progressive degenerative pathologies.[2,6,7,8] From the clinical standpoint, human diseases caused by mitochondrial impairment exhibit heterogeneous manifestations that range from single tissue lesions to multiple organ failure
Our findings suggest that defective oxidative phosphorylation (OXPHOS) leads to dendritic branching through the modulation of the AMPK/PI3K signaling pathway (Figure 4d)
Mitochondrial function significantly contributes to the maintenance of both pre- and postsynaptic compartments, affecting existing synapses as well as the formation of new ones.[27,28]
Summary
Given their essential role in cellular metabolism, genetically inherited mutations as well as off-target effects of chemical compounds that disturb mitochondrial functions can seriously impinge healthy lifespan and inevitably lead to severe syndromes or progressive degenerative pathologies.[2,6,7,8] From the clinical standpoint, human diseases caused by mitochondrial impairment exhibit heterogeneous manifestations that range from single tissue lesions to multiple organ failure. The discovery that several inherited forms of brain disorders are due to mutations in genes involved in mitochondrial activity supports this view.[10] Yet, how OXPHOS impairment can affect neuronal activity, neural branching and the plasticity of neural circuits remains an important open question. The two sensory PVD neurons in the body and the two FLP neurons in the head of the animal display highly branched dendrites.[12] Given their similarity with mammalian neurons and the suitability of nematodes for genetic analysis, these two classes of neurons have been extensively studied to unveil evolutionarily conserved signaling pathways involved in cell fate specification and morphogenesis. We propose the AMPK/PI3K axis as a critical regulator of dendritic remodeling in conditions of compromised mitochondrial function
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