Astrocytes, often considered as secondary responders to neurodegeneration, are emerging as primary drivers of brain disease. Here we show that mitochondrial DNA depletion in astrocytes affects their primary cilium, the signaling organelle of a cell. The progressive oxidative phosphorylation deficiency in astrocytes induces FOXJ1 and RFX transcription factors, known as master regulators of motile ciliogenesis. Consequently, a robust gene expression program involving motile cilia components and multiciliated cell differentiation factors are induced. While the affected astrocytes still retain a single cilium, these organelles elongate and become remarkably distorted. The data suggest that chronic activation of the mitochondrial integrated stress response (ISRmt) in astrocytes drives anabolic metabolism and promotes ciliary elongation. Collectively, our evidence indicates that an active signaling axis involving mitochondria and primary cilia exists and that ciliary signaling is part of ISRmt in astrocytes. We propose that metabolic ciliopathy is a novel pathomechanism for mitochondria-related neurodegenerative diseases.

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.