Mitochondrial dysfunction compromises ciliary homeostasis in astrocytes

Reactive astrogliosis is a key component of neurological diseases. However, the active roles of astrocytes in pathogenic mechanisms and the involved molecular pathways are insufficiently understood. Here, we show that mitochondrial DNA depletion in astrocytes, causing mitochondrial spongiotic encephalopathy in mice, challenges the maintenance of primary cilium, the major cellular sensory organelle, which relays external signals to intracellular pathways. We show that mitochondrial respiratory chain deficiency in astrocytes induces FOXJ1 and RFX transcription factors, the master regulators of motile ciliogenesis, and consequently an aberrant nuclear expression program of motile cilia components. While the astrocytes still retain their single primary cilia, these organelles elongate and become remarkably distorted. Yet, respiratory chain deficiency in multiciliated ependymal cells does not cause overt cilia morphology defects. Collectively, our evidence points to an active signaling axis between astrocyte mitochondria and primary cilia. Furthermore, our data introduce metabolic ciliopathy as a pathomechanism for mitochondria-related neurodegenerative diseases.