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Mitochondria form cholesterol-rich contact sites with the nucleus during retrograde response

Desai, R; East, D A; Hardy, L; Crosby, J; Faccenda, D; Alvarex, M S; Mainenti, M; Kuhlman Hussy, L; Bentham, R; Szabadkai, G; Zappulli, V; Dhoot, G; Fleck, R A; Vizcay-Barrena, G; Smith, K; Campanella, M

Authors

R Desai

D A East

L Hardy

J Crosby

D Faccenda

M S Alvarex

M Mainenti

L Kuhlman Hussy

R Bentham

G Szabadkai

V Zappulli

G Dhoot

R A Fleck

G Vizcay-Barrena

K Smith

M Campanella



Abstract

Cholesterol metabolism is pivotal to cellular homeostasis, hormones production, and membranes composition. Its dysregulation associates with malignant reprogramming and therapy resistance. Cholesterol is trafficked into the mitochondria for steroidogenesis by the transduceome protein complex, which assembles on the outer mitochondrial membrane (OMM). The highly conserved, cholesterol-binding, stress-reactive, 18kDa translocator protein (TSPO), is a key component of this complex. Here, we modulate TSPO to study the process of mitochondrial retrograde signalling with the nucleus, by dissecting the role played by cholesterol and its oxidized forms. Using confocal and ultrastructural imaging, we describe that TSPO enriched mitochondria, remodel around the nucleus, gathering in cholesterol-enriched domains (or contact sites). This communication is controlled by HMG-CoA reductase inhibitors (statins), molecular and pharmacological regulation of TSPO. The described Nucleus-Associated Mitochondria (NAM) seem to be implementing survival signalling in aggressive forms of breast cancer. This work therefore provides the first evidence for a functional and bio-mechanical tethering between mitochondria and nucleus, as being the basis of pro-survival mechanisms, thus establishing a new paradigm in cross-organelle communication via cholesterol re-distribution.

Citation

Desai, R., East, D. A., Hardy, L., Crosby, J., Faccenda, D., Alvarex, M. S., …Campanella, M. (2020). Mitochondria form cholesterol-rich contact sites with the nucleus during retrograde response. Science Advances, https://doi.org/10.1101/445411

Journal Article Type Article
Acceptance Date Nov 13, 2020
Publication Date Dec 18, 2020
Deposit Date Nov 3, 2018
Publicly Available Date Dec 21, 2020
Journal Science Advances
Publisher American Association for the Advancement of Science
Peer Reviewed Peer Reviewed
DOI https://doi.org/10.1101/445411
Public URL https://rvc-repository.worktribe.com/output/1385543

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