MICAL2PV suppresses the formation of tunneling nanotubes and modulates mitochondrial trafficking

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

doi:10.15252/embr.202052006

Cited by 28 publications

(26 citation statements)

References 99 publications

(162 reference statements)

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“…Immunofluorescence staining was performed following our published protocol 41 using a polyclonal rabbit anti-PGS1(Sigma-Aldrich, Cat# AV48896) and secondary antibody conjugated with Alexa-488 (Abcam, Cat# ab150081).…”

Section: Methodsmentioning

confidence: 99%

“…The control shRNA construct (shCtr) was as previously described 41 . A shPGS1 construct was designed to express shRNA against PGS1 (target sequence: 5'-TCGGGTTCCATCCGTTTAAAT-3') in the plasmid vector Tet-pLKO-puro (Vector Builder Inc) to specifically down-regulate expression of PGS1following induction with tetracycline (Tet).…”

Section: Sample Preparation Hek293 Cell Culturesmentioning

confidence: 99%

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Multi-Molecular Hyperspectral PRM-SRS Imaging

Shi

Zhang

et al. 2022

Preprint

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Lipids play crucial roles in many biological processes under physiological and pathological conditions. Mapping spatial distribution and examining metabolic dynamics of different lipids in cells and tissues in situ are critical for understanding aging and diseases. Commonly used imaging methods, including mass spectrometry-based technologies or labeled imaging techniques, tend to disrupt the native environment of cells/tissues and have limited spatial or spectral resolution, while traditional optical imaging techniques still lack the capacity to distinguish chemical differences between lipid subtypes. To overcome these limitations, we developed a new hyperspectral imaging platform that integrates a Penalized Reference Matching algorithm with Stimulated Raman Scattering (PRM-SRS) microscopy. With this new approach, we directly visualized and identified multiple lipid species in cells and tissues in situ with high chemical specificity and subcellular resolution. High density lipoprotein (HDL) particles containing non-esterified cholesterol was observed in the kidney, indicating that these pools of cholesterol are ectopic deposits, or have yet to be enriched. We detected a higher Cholesterol to phosphatidylethanolamine (PE) ratio inside the granule cells of hippocampal samples in old mice, suggesting altered membrane lipid synthesis and metabolism in aging brains. PRM-SRS imaging also revealed subcellular distributions of sphingosine and cardiolipin in the human brain sample. Compared with other techniques, PRM-SRS demonstrates unique advantages, including faster data processing and direct user-defined visualization with enhanced chemical specificity for distinguishing clinically relevant lipid subtypes in different organs and species. Our method has broad applications in multiplexed cell and tissue imaging.

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Section: Methodsmentioning

confidence: 99%

Section: Sample Preparation Hek293 Cell Culturesmentioning

confidence: 99%

Multi-Molecular Hyperspectral PRM-SRS Imaging

Shi

Zhang

et al. 2022

Preprint

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“…Miro proteins provide tethering of mitochondria to cytoskeletal motor proteins and serve as regulators of transport of the organelles, based on their calcium-dependent activity (Eberhardt et al, 2020;Nahacka et al, 2021). Essential role of Miro in intercellular transfer of mitochondria has been demonstrated by many studies reporting a correlation between Miro expression and mitochondria exchange with TNTs being the conduits for the transport (Ahmad et al, 2014;Babenko et al, 2018;English et al, 2020;Tseng et al, 2021;Wang et al, 2021). Except for one study, presence of Miro was found essential for the transfer/movement of mitochondria along TNTs rather than for their formation (Babenko et al, 2018;Raghavan et al, 2021).…”

Section: Mechanism Of Mitochondrial Transfer Via Tnts and The Role Of...mentioning

confidence: 99%

“…Additionally Miro1 and partially Miro2 have been shown to be important for mitochondrial transport towards the cell periphery, especially in case of energy-demanding processes such as migration and invasion of cancer cells ( Caino et al, 2016 ; Lopez-Domenech et al, 2018 ; Wang et al, 2021 ). Knock-out of these two proteins results in perinuclear localization of mitochondria, with more prominent phenotype in case of Miro1/Miro2 double knock-out ( Kittler, 2015 ).…”

Section: Tunneling Nanotubesmentioning

confidence: 99%

Miro proteins and their role in mitochondrial transfer in cancer and beyond

Nahácka

Novák

Zobalova

et al. 2022

Front. Cell Dev. Biol.

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Mitochondria are organelles essential for tumor cell proliferation and metastasis. Although their main cellular function, generation of energy in the form of ATP is dispensable for cancer cells, their capability to drive their adaptation to stress originating from tumor microenvironment makes them a plausible therapeutic target. Recent research has revealed that cancer cells with damaged oxidative phosphorylation import healthy (functional) mitochondria from surrounding stromal cells to drive pyrimidine synthesis and cell proliferation. Furthermore, it has been shown that energetically competent mitochondria are fundamental for tumor cell migration, invasion and metastasis. The spatial positioning and transport of mitochondria involves Miro proteins from a subfamily of small GTPases, localized in outer mitochondrial membrane. Miro proteins are involved in the structure of the MICOS complex, connecting outer and inner-mitochondrial membrane; in mitochondria-ER communication; Ca2+ metabolism; and in the recycling of damaged organelles via mitophagy. The most important role of Miro is regulation of mitochondrial movement and distribution within (and between) cells, acting as an adaptor linking organelles to cytoskeleton-associated motor proteins. In this review, we discuss the function of Miro proteins in various modes of intercellular mitochondrial transfer, emphasizing the structure and dynamics of tunneling nanotubes, the most common transfer modality. We summarize the evidence for and propose possible roles of Miro proteins in nanotube-mediated transfer as well as in cancer cell migration and metastasis, both processes being tightly connected to cytoskeleton-driven mitochondrial movement and positioning.

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“…A recent study has shown that the monooxygenase domain of MICAL2PV, a spliced isoform product of the neuronal guidance gene MICAL2, interacts with Miro-2, inhibiting TNT formation by depolymerization of f-actin. MICAL2PV plays crucial role in cell survival and down-regulation of MICAL2PV, and protect lung cancer cells treated with chemotherapeutic drugs [ 123 ].…”

Section: Rho Gtpase Related Signals Counteract Apoptosis Via Tunnelling Nanotubesmentioning

confidence: 99%

Oxidative stress and Rho GTPases in the biogenesis of tunnelling nanotubes: implications in disease and therapy

Raghavan

Rao

Neužil

et al. 2021

Cell. Mol. Life Sci.

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Tunnelling nanotubes (TNTs) are an emerging route of long-range intercellular communication that mediate cell-to-cell exchange of cargo and organelles and contribute to maintaining cellular homeostasis by balancing diverse cellular stresses. Besides their role in intercellular communication, TNTs are implicated in several ways in health and disease. Transfer of pathogenic molecules or structures via TNTs can promote the progression of neurodegenerative diseases, cancer malignancy, and the spread of viral infection. Additionally, TNTs contribute to acquiring resistance to cancer therapy, probably via their ability to rescue cells by ameliorating various pathological stresses, such as oxidative stress, reactive oxygen species (ROS), mitochondrial dysfunction, and apoptotic stress. Moreover, mesenchymal stem cells play a crucial role in the rejuvenation of targeted cells with mitochondrial heteroplasmy and oxidative stress by transferring healthy mitochondria through TNTs. Recent research has focussed on uncovering the key regulatory molecules involved in the biogenesis of TNTs. However further work will be required to provide detailed understanding of TNT regulation. In this review, we discuss possible associations with Rho GTPases linked to oxidative stress and apoptotic signals in biogenesis pathways of TNTs and summarize how intercellular trafficking of cargo and organelles, including mitochondria, via TNTs plays a crucial role in disease progression and also in rejuvenation/therapy.

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MICAL2PV suppresses the formation of tunneling nanotubes and modulates mitochondrial trafficking

Cited by 28 publications

References 99 publications

Multi-Molecular Hyperspectral PRM-SRS Imaging

Multi-Molecular Hyperspectral PRM-SRS Imaging

Miro proteins and their role in mitochondrial transfer in cancer and beyond

Oxidative stress and Rho GTPases in the biogenesis of tunnelling nanotubes: implications in disease and therapy

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