The adaptor protein Miro1 modulates horizontal transfer of mitochondria in mouse melanoma models

Authors:

Jaromir Novak, Zuzana Nahacka, Gabriela L. Oliveira, Petra Brisudova, Maria Dubisova, Sarka Dvorakova, Sona Miklovicova, Marketa Dalecka, Verena Puttrich, Lenka Grycova, Silvia Magalhaes-Novais, Catarina Mendes Correia, Jennifer Levoux, Ludek Stepanek, Jan Prochazka, David Svec, David Pajuelo Reguera, Guillermo Lopez-Domenech, Renata Zobalova, Radek Sedlacek, Mikkel G. Terp, Payam A. Gammage, Zdenek Lansky, Josef Kittler, Paulo J. Oliveira, Henrik J. Ditzel, Michael V. Berridge, Anne-Marie Rodriguez, Stepana Boukalova, Jakub Rohlena, Jiri Neuzil

Keywords:

Miro1; RHOT1; cancer; melanoma; mitochondria; horizontal transfer of mitochondria; tunneling nanotubes

Abstract:

Recent research has shown that mtDNA-deficient cancer cells (ρ⁰ cells) acquire mitochondria from tumor stromal cells to restore respiration, facilitating tumor formation. We investigated the role of Miro1, an adaptor protein involved in movement of mitochondria along microtubules, in this phenomenon. Inducible Miro1 knockout (Miro1^KO) mice markedly delayed tumor formation after grafting ρ⁰ cancer cells. Miro1^KO mice with fluorescently labeled mitochondria revealed that this delay was due to hindered mitochondrial transfer from the tumor stromal cells to grafted B16 ρ⁰ cells, which impeded recovery of mitochondrial respiration and tumor growth. Miro1^KO led to the perinuclear accumulation of mitochondria and impaired mobility of the mitochondrial network. In vitro experiments revealed decreased association of mitochondria with microtubules, compromising mitochondrial transfer via tunneling nanotubes (TNTs) in mesenchymal stromal cells. Here we show the role of Miro1 in horizontal mitochondrial transfer in mouse melanoma models in vivo and its involvement with TNTs.

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