RT Journal Article
SR Electronic
T1 Mitochondria form cholesterol tethered contact sites with the Nucleus to regulate retrograde response
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 445411
DO 10.1101/445411
A1 Radha Desai
A1 Daniel A East
A1 Liana Hardy
A1 James Crosby
A1 Manuel Rigon
A1 Danilo Faccenda
A1 María Soledad Alvarez
A1 Arti Singh
A1 Marta Mainenti
A1 Laura Kuhlman Hussey
A1 Robert Bentham
A1 Gyorgy Szabadkai
A1 Valentina Zappulli
A1 Gurtej Dhoot
A1 Lisa E Romano
A1 Xia Dong
A1 Anne Hamechar-Brady
A1 J Paul Chapple
A1 Roland A. Fleck
A1 Gema Vizcay-Barrena
A1 Kenneth Smith
A1 Michelangelo Campanella
YR 2019
UL http://biorxiv.org/content/early/2019/04/04/445411.abstract
AB Cholesterol metabolism is pivotal to cellular homeostasis, hormone production, and membrane composition. Its dysregulation is associated with malignant reprogramming and therapy resistance in neoplastic progression. 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, forming cholesterol-enriched domains (or contact sites). This dynamic is controlled by the molecular and pharmacological modulation of TSPO, which is required to establish the Nucleus-Associated Mitochondria (NAM) and hence implement pro-survival signalling in aggressive forms of breast cancer. This work provides the first evidence for a functional and biomechanical tethering between mitochondria and nucleus thus establishing a new paradigm in cross-organelle communication.