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

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

doi:10.1038/s41419-019-2184-y

Cited by 58 publications

(72 citation statements)

References 39 publications

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“…An interesting possibility is that ciliogenesis and Hh signaling may also contribute to the cytoprotective functions of NRF2. Consistent with this, several reports indicate that redox stress affects primary cilia and Hh signaling, which in turn protect cells against such stress [ 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ].…”

Section: Discussionsupporting

confidence: 70%

“…In many of these diseases, a prominent role is played by redox, proteostatic and other kinds of cellular stress [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ]. Consistently, primary cilia and Hh signaling can respond to redox and other stress signals, and their function may also protect cells from such stresses [ 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ]. In this context, recent findings connecting primary cilia and Hh signaling to NRF2 (nuclear factor erythroid 2-related factor 2) are of special relevance.…”

Section: Primary Cilia As Cellular Antennaementioning

confidence: 99%

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NRF2 and Primary Cilia: An Emerging Partnership

et al. 2020

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When not dividing, many cell types target their centrosome to the plasma membrane, where it nucleates assembly of a primary cilium, an antenna-like signaling structure consisting of nine concentric microtubule pairs surrounded by membrane. Primary cilia play important pathophysiological roles in many tissues, their dysfunction being associated with cancer and ciliopathies, a diverse group of congenital human diseases. Several recent studies have unveiled functional connections between primary cilia and NRF2 (nuclear factor erythroid 2-related factor 2), the master transcription factor orchestrating cytoprotective responses to oxidative and other cellular stresses. These NRF2-cilia relationships are reciprocal: primary cilia, by promoting autophagy, downregulate NRF2 activity. In turn, NRF2 transcriptionally regulates genes involved in ciliogenesis and Hedgehog (Hh) signaling, a cilia-dependent pathway with major roles in embryogenesis, stem cell function and tumorigenesis. Nevertheless, while we found that NRF2 stimulates ciliogenesis and Hh signaling, a more recent study reported that NRF2 negatively affects these processes. Herein, we review the available evidence linking NRF2 to primary cilia, suggest possible explanations to reconcile seemingly contradictory data, and discuss what the emerging interplay between primary cilia and NRF2 may mean for human health and disease.

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Section: Discussionsupporting

confidence: 70%

Section: Primary Cilia As Cellular Antennaementioning

confidence: 99%

NRF2 and Primary Cilia: An Emerging Partnership

et al. 2020

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“…Increased autophagy may generate the higher amino acid levels after hypoxia (Table 2) to use them for the substrate-level ADP phosphorylation in the hypoxic brain of non-pregnant rats. Autophagy is also coupled to pro-survival function of mitochondrial fission under energy stress [44][45][46][47]. However, the homeostatic and pro-survival functions of mTOR, autophagy and mitochondrial fission are highly conditional, with overactivation of these processes also mediating the brain damage by hypoxia [48][49][50].…”

Section: Discussionmentioning

confidence: 99%

Hypoxic Adaptation of Mitochondrial Metabolism in Rat Cerebellum Decreases in Pregnancy

Граф

Trofimova

Ksenofontov

et al. 2020

Cells

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Function of brain amino acids as neurotransmitters or their precursors implies changes in the amino acid levels and/or metabolism in response to physiological and environmental challenges. Modelling such challenges by pregnancy and/or hypoxia, we characterize the amino acid pool in the rat cerebellum, quantifying the levels and correlations of 15 amino acids and activity of 2-oxoglutarate dehydrogenase complex (OGDHC). The parameters are systemic indicators of metabolism because OGDHC limits the flux through mitochondrial TCA cycle, where amino acids are degraded and their precursors synthesized. Compared to non-pregnant state, pregnancy increases the cerebellar content of glutamate and tryptophan, decreasing interdependence between the quantified components of amino acid metabolism. In response to hypoxia, the dependence of cerebellar amino acid pool on OGDHC and the average levels of arginine, glutamate, lysine, methionine, serine, phenylalanine, and tryptophan increase in non-pregnant rats only. This is accompanied by a higher hypoxic resistance of the non-pregnant vs. pregnant rats, pointing to adaptive significance of the hypoxia-induced changes in the cerebellar amino acid metabolism. These adaptive mechanisms are not effective in the pregnancy-changed metabolic network. Thus, the cerebellar amino acid levels and OGDHC activity provide sensitive markers of the physiology-dependent organization of metabolic network and its stress adaptations.

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“…At this point, we cannot rule out that ion flow through Kv10.1 is only a part of the signaling mechanism. Active Kv10.1 channels participate in primary cilium disassembly [16,43], a process that is also impaired by mitochondrial stress [44]. Both ciliary homeostasis [45] and mitochondrial dynamics [46] require calcium signaling, and active potassium channels hyperpolarize the membrane, increasing the driving force for calcium to enter the cells.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Kv10.1 Channels Sensitizes Mitochondria of Cancer Cells to Antimetabolic Agents

Hernández‐Reséndiz

Pacheu-Grau

Sánchez

et al. 2020

Cancers

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Reprogramming of energy metabolism constitutes one of the hallmarks of cancer and is, therefore, an emerging therapeutic target. We describe here that the potassium channel Kv10.1, which is frequently overexpressed in primary and metastatic cancer, and has been proposed a therapeutic target, participates in metabolic adaptation of cancer cells through regulation of mitochondrial dynamics. We used biochemical and cell biological techniques, live cell imaging and high-resolution microscopy, among other approaches, to study the impact of Kv10.1 on the regulation of mitochondrial stability. Inhibition of Kv10.1 expression or function led to mitochondrial fragmentation, increase in reactive oxygen species and increased autophagy. Cells with endogenous overexpression of Kv10.1 were also more sensitive to mitochondrial metabolism inhibitors than cells with low expression, indicating that they are more dependent on mitochondrial function. Consistently, a combined therapy using functional monoclonal antibodies for Kv10.1 and mitochondrial metabolism inhibitors resulted in enhanced efficacy of the inhibitors. Our data reveal a new mechanism regulated by Kv10.1 in cancer and a novel strategy to overcome drug resistance in cancers with a high expression of Kv10.1.

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

Cited by 58 publications

References 39 publications

NRF2 and Primary Cilia: An Emerging Partnership

NRF2 and Primary Cilia: An Emerging Partnership

Hypoxic Adaptation of Mitochondrial Metabolism in Rat Cerebellum Decreases in Pregnancy

Inhibition of Kv10.1 Channels Sensitizes Mitochondria of Cancer Cells to Antimetabolic Agents

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