MICAL2PV suppresses the formation of tunneling nanotubes and modulates mitochondrial trafficking

Fei Wang; Xiaoping Chen; Haipeng Cheng; Lu Song; Jianghong Liu; Steve Caplan; Li Zhu; Jane Y. Wu

doi:10.15252/embr.202052006

MICAL2PV suppresses the formation of tunneling nanotubes and modulates mitochondrial trafficking

Fei Wang, Xiaoping Chen, Haipeng Cheng, Lu Song, Jianghong Liu, Steve Caplan, Li Zhu^*, Jane Y. Wu^*

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

Abstract

Tunneling nanotubes (TNTs) are actin-rich structures that connect two or more cells and mediate cargo exchange between spatially separated cells. TNTs transport signaling molecules, vesicles, organelles, and even pathogens. However, the molecular mechanisms regulating TNT formation remain unclear and little is known about the endogenous mechanisms suppressing TNT formation in lung cancer cells. Here, we report that MICAL2PV, a splicing isoform of the neuronal guidance gene MICAL2, is a novel TNT regulator that suppresses TNT formation and modulates mitochondrial distribution. MICAL2PV interacts with mitochondrial Rho GTPase Miro2 and regulates subcellular mitochondrial trafficking. Moreover, down-regulation of MICAL2PV enhances survival of cells treated with chemotherapeutical drugs. The monooxygenase (MO) domain of MICAL2PV is required for its activity to inhibit TNT formation by depolymerizing F-actin. Our data demonstrate a previously unrecognized function of MICAL2 in TNT formation and mitochondrial trafficking. Furthermore, our study uncovers a role of the MICAL2PV-Miro2 axis in mitochondrial trafficking, providing a mechanistic explanation for MICAL2PV activity in suppressing TNT formation and in modulating mitochondrial subcellular distribution.

Original language	English (US)
Article number	e52006
Journal	EMBO Reports
Volume	22
Issue number	7
DOIs	https://doi.org/10.15252/embr.202052006
State	Published - Jul 5 2021

Funding

We are grateful to Dr. P. Aspenström for the gift of plasmids. We thank Dr. William A. Muller and members of the Wu laboratory for discussions, suggestions, and critical reading of the manuscript. We thank Dr. Yang Li for his expert suggestions on the quantification of immunofluorescent images. FW, LS, JL, and LZ are supported by grants from the National Key R&D Development Program of China (2019YFA0508603) and the National Natural Science Foundation of China (31971075 and 31671174). The work was supported by National Institutes of Health (R01CA175360 to JW; R01GM123557; P30GM106397 to SC).

Keywords

F-actin
Miro2
lung cancer
mitochondria
tunneling nanotubes

ASJC Scopus subject areas

Genetics
Molecular Biology
Biochemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.15252/embr.202052006

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title = "MICAL2PV suppresses the formation of tunneling nanotubes and modulates mitochondrial trafficking",

abstract = "Tunneling nanotubes (TNTs) are actin-rich structures that connect two or more cells and mediate cargo exchange between spatially separated cells. TNTs transport signaling molecules, vesicles, organelles, and even pathogens. However, the molecular mechanisms regulating TNT formation remain unclear and little is known about the endogenous mechanisms suppressing TNT formation in lung cancer cells. Here, we report that MICAL2PV, a splicing isoform of the neuronal guidance gene MICAL2, is a novel TNT regulator that suppresses TNT formation and modulates mitochondrial distribution. MICAL2PV interacts with mitochondrial Rho GTPase Miro2 and regulates subcellular mitochondrial trafficking. Moreover, down-regulation of MICAL2PV enhances survival of cells treated with chemotherapeutical drugs. The monooxygenase (MO) domain of MICAL2PV is required for its activity to inhibit TNT formation by depolymerizing F-actin. Our data demonstrate a previously unrecognized function of MICAL2 in TNT formation and mitochondrial trafficking. Furthermore, our study uncovers a role of the MICAL2PV-Miro2 axis in mitochondrial trafficking, providing a mechanistic explanation for MICAL2PV activity in suppressing TNT formation and in modulating mitochondrial subcellular distribution.",

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author = "Fei Wang and Xiaoping Chen and Haipeng Cheng and Lu Song and Jianghong Liu and Steve Caplan and Li Zhu and Wu, {Jane Y.}",

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doi = "10.15252/embr.202052006",

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AU - Wang, Fei

AU - Chen, Xiaoping

AU - Cheng, Haipeng

AU - Song, Lu

AU - Liu, Jianghong

AU - Caplan, Steve

AU - Zhu, Li

AU - Wu, Jane Y.

PY - 2021/7/5

Y1 - 2021/7/5

N2 - Tunneling nanotubes (TNTs) are actin-rich structures that connect two or more cells and mediate cargo exchange between spatially separated cells. TNTs transport signaling molecules, vesicles, organelles, and even pathogens. However, the molecular mechanisms regulating TNT formation remain unclear and little is known about the endogenous mechanisms suppressing TNT formation in lung cancer cells. Here, we report that MICAL2PV, a splicing isoform of the neuronal guidance gene MICAL2, is a novel TNT regulator that suppresses TNT formation and modulates mitochondrial distribution. MICAL2PV interacts with mitochondrial Rho GTPase Miro2 and regulates subcellular mitochondrial trafficking. Moreover, down-regulation of MICAL2PV enhances survival of cells treated with chemotherapeutical drugs. The monooxygenase (MO) domain of MICAL2PV is required for its activity to inhibit TNT formation by depolymerizing F-actin. Our data demonstrate a previously unrecognized function of MICAL2 in TNT formation and mitochondrial trafficking. Furthermore, our study uncovers a role of the MICAL2PV-Miro2 axis in mitochondrial trafficking, providing a mechanistic explanation for MICAL2PV activity in suppressing TNT formation and in modulating mitochondrial subcellular distribution.

AB - Tunneling nanotubes (TNTs) are actin-rich structures that connect two or more cells and mediate cargo exchange between spatially separated cells. TNTs transport signaling molecules, vesicles, organelles, and even pathogens. However, the molecular mechanisms regulating TNT formation remain unclear and little is known about the endogenous mechanisms suppressing TNT formation in lung cancer cells. Here, we report that MICAL2PV, a splicing isoform of the neuronal guidance gene MICAL2, is a novel TNT regulator that suppresses TNT formation and modulates mitochondrial distribution. MICAL2PV interacts with mitochondrial Rho GTPase Miro2 and regulates subcellular mitochondrial trafficking. Moreover, down-regulation of MICAL2PV enhances survival of cells treated with chemotherapeutical drugs. The monooxygenase (MO) domain of MICAL2PV is required for its activity to inhibit TNT formation by depolymerizing F-actin. Our data demonstrate a previously unrecognized function of MICAL2 in TNT formation and mitochondrial trafficking. Furthermore, our study uncovers a role of the MICAL2PV-Miro2 axis in mitochondrial trafficking, providing a mechanistic explanation for MICAL2PV activity in suppressing TNT formation and in modulating mitochondrial subcellular distribution.

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MICAL2PV suppresses the formation of tunneling nanotubes and modulates mitochondrial trafficking

Abstract

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Keywords

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UN SDGs

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