Primary cilia mediate mitochondrial stress responses to promote dopamine neuron survival in a Parkinson\u2019s disease model

Ji-Eun Bae,Keetae Kim,Doo Sin Jo,Gil Myung Kang,Yong-Keun Jung,Min-Seon Kim,Dong-Hyung Cho,Se Hee Min

doi:10.1038/s41419-019-2184-y

Abstract

A primary cilium is an antenna-like structure on the cell surface that plays a crucial role in sensory perception and signal transduction. Mitochondria, the ‘powerhouse’ of the cell, control cell survival, and death. The cellular ability to remove dysfunctional mitochondria through mitophagy is important for cell survival. We show here that mitochondrial stress, caused by respiratory complex inhibitors and excessive fission, robustly stimulates ciliogenesis in different types of cells including neuronal cells. Mitochondrial stress-induced ciliogenesis is mediated by mitochondrial reactive oxygen species generation, subsequent activation of AMP-activated protein kinase and autophagy. Conversely, abrogation of ciliogenesis compromises mitochondrial stress-induced autophagy, leading to enhanced cell death. In mice, treatment with mitochondrial toxin, MPTP elicits ciliary elongation and autophagy in the substantia nigra dopamine neurons. Blockade of cilia formation in these neurons attenuates MPTP-induced autophagy but facilitates dopamine neuronal loss and motor disability. Our findings demonstrate the important role of primary cilia in cellular pro-survival responses during mitochondrial stress.

Highlights

An evolutionally-conserved organelle, the primary cilium, was once thought to be non-functional but is considered a pivotal signaling center, associated with 15 signaling pathways including Hedgehog (Hh)[1,2]
In accordance with the previous notion, we found that treatment with rotenone, MPP+, or carbonyl cyanide m-chlorophenyl hydrazine (CCCP) induced massive mitochondrial fragmentation and depolarization of the mitochondrial membrane potential (Fig. 1b, c)
Based on the result of this study, we propose that both Mitochondrial-derived ROS (mtROS)- and AMPK-driven autophagy are major mechanisms underlying mitochondrial stress-induced ciliogenesis (Figs. 3 and 4)

Summary

Introduction

An evolutionally-conserved organelle, the primary cilium, was once thought to be non-functional but is considered a pivotal signaling center, associated with 15 signaling pathways including Hedgehog (Hh)[1,2]. During the assembly stage of the primary cilium, ciliatargeting proteins are transported from the Golgi to the basal body via vesicular transport, and to the ciliary tip along the axoneme via intraflagellar transport (IFT)[1]. Mitochondria, essential organelles for both cell survival and death continuously undergo balanced fission and Autophagy is a catabolic process that degrades organelles and long-lived proteins and maintains cellular homeostasis by regulating the cellular energy balance and facilitating organelle quality control[5]. The autophagic machinery is highly sensitive to intracellular and extracellular stress cues[5]. The adaptive autophagy mechanism is a part of an integrated series of responses by which cells respond to stress stimuli[5]. Recent studies have elucidated a close reciprocal relationship between primary cilia and the autophagic machinery.

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Results

Conclusion