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Mitochondrial dysfunction compromises ciliary homeostasis in astrocytes.

ABSTRACT: 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.

SUBMITTER: Ignatenko O

PROVIDER: S-EPMC9674092 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Mitochondrial dysfunction compromises ciliary homeostasis in astrocytes.

Ignatenko Olesia O Malinen Satu S Rybas Sofiia S Vihinen Helena H Nikkanen Joni J Kononov Aleksander A Jokitalo Eija S ES Ince-Dunn Gulayse G Suomalainen Anu A

The Journal of cell biology 20221116 1

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 mu ...[more]

PMID: 36383135

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Mitochondrial dysfunction compromises ciliary homeostasis in astrocytes.

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Mitochondrial dysfunction compromises ciliary homeostasis in astrocytes.

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