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5. Mitochondria form contact sites with the nucleus to couple prosurvival retrograde response

Author

Desai, Radha, primary, East, Daniel A., additional, Hardy, Liana, additional, Faccenda, Danilo, additional, Rigon, Manuel, additional, Crosby, James, additional, Alvarez, María Soledad, additional, Singh, Aarti, additional, Mainenti, Marta, additional, Hussey, Laura Kuhlman, additional, Bentham, Robert, additional, Szabadkai, Gyorgy, additional, Zappulli, Valentina, additional, Dhoot, Gurtej K., additional, Romano, Lisa E., additional, Xia, Dong, additional, Coppens, Isabelle, additional, Hamacher-Brady, Anne, additional, Chapple, J. Paul, additional, Abeti, Rosella, additional, Fleck, Roland A., additional, Vizcay-Barrena, Gema, additional, Smith, Kenneth, additional, and Campanella, Michelangelo, additional

Published
2020
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6. Aberrant ribonucleotide incorporation and multiple deletions in mitochondrial DNA of the murine MPV17 disease model

Author

Moss, Chloe F, Dalla Rosa, Ilaria, Hunt, Lilian E, Yasukawa, Takehiro, Young, Robert, Jones, Aleck W E, Reddy, Kaalak, Desai, Radha, Virtue, Sam, Elgar, Greg, Voshol, Peter, Taylor, Martin S, Holt, Ian J, Reijns, Martin A M, and Spinazzola, Antonella

Subjects
Mice, Knockout, Mitochondrial Diseases, Base Sequence, Brain, Membrane Proteins, Genome Integrity, Repair and Replication, Ribonucleotides, DNA, Mitochondrial, Cell Line, Mice, Inbred C57BL, Mitochondrial Proteins, Disease Models, Animal, Liver, Cell Line, Tumor, Journal Article, Animals, Humans, Sequence Deletion
Abstract

All DNA polymerases misincorporate ribonucleotides despite their preference for deoxyribonucleotides, and analysis of cultured cells indicates that mammalian mitochondrial DNA (mtDNA) tolerates such replication errors. However, it is not clear to what extent misincorporation occurs in tissues, or whether this plays a role in human disease. Here, we show that mtDNA of solid tissues contains many more embedded ribonucleotides than that of cultured cells, consistent with the high ratio of ribonucleotide to deoxynucleotide triphosphates in tissues, and that riboadenosines account for three-quarters of them. The pattern of embedded ribonucleotides changes in a mouse model of Mpv17 deficiency, which displays a marked increase in rGMPs in mtDNA. However, while the mitochondrial dGTP is low in the Mpv17−/− liver, the brain shows no change in the overall dGTP pool, leading us to suggest that Mpv17 determines the local concentration or quality of dGTP. Embedded rGMPs are expected to distort the mtDNA and impede its replication, and elevated rGMP incorporation is associated with early-onset mtDNA depletion in liver and late-onset multiple deletions in brain of Mpv17−/− mice. These findings suggest aberrant ribonucleotide incorporation is a primary mtDNA abnormality that can result in pathology.

Published
2017
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7. Mitochondria form cholesterol tethered contact sites with the Nucleus to regulate retrograde response

Author

Desai, Radha, East, Daniel A, Hardy, Liana, Crosby, James, Rigon, Manuel, Faccenda, Danilo, Alvarez, María Soledad, Singh, Arti, Mainenti, Marta, Hussey, Laura Kuhlman, Bentham, Robert, Szabadkai, Gyorgy, Zappulli, Valentina, Dhoot, Gurtej, Romano, Lisa E, Dong, Xia, Hamechar-Brady, Anne, Chapple, J Paul, Fleck, Roland A., Vizcay-Barrena, Gema, Smith, Kenneth, and Campanella, Michelangelo

Abstract

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.

Published
2018
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9. Mitochondria Form Contact Sites with the Nucleus to Couple Pro-Survival Retrograde Response

Author

Desai, Radha, primary, East, Daniel A., additional, Hardy, Liana, additional, Crosby, James, additional, Rigon, Manuel, additional, Faccenda, Danilo, additional, Alvarez, Maria Soledad, additional, Singh, Aarti, additional, Mainenti, Marta, additional, Hussey, Laura Kuhlman, additional, Bentham, Robert, additional, Szabadkai, Gyorgy, additional, Zappulli, Valentina, additional, Dhoot, Gurtej, additional, Romano, Lisa E., additional, Dong, Xia, additional, Hamechar-Brady, Anne, additional, Chapple, J. Paul, additional, Abeti, Rosella, additional, Fleck, Roland A., additional, Vizcay-Barrena, Gema, additional, Smith, Kenneth, additional, and Campanella, Michelangelo, additional

Published
2019
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10. Transglutaminase Type 2 Regulates ER-Mitochondria Contact Sites by Interacting with GRP75

Author

D’Eletto, Manuela, primary, Rossin, Federica, additional, Occhigrossi, Luca, additional, Farrace, Maria Grazia, additional, Faccenda, Danilo, additional, Desai, Radha, additional, Marchi, Saverio, additional, Refolo, Giulia, additional, Falasca, Laura, additional, Antonioli, Manuela, additional, Ciccosanti, Fabiola, additional, Fimia, Gian Maria, additional, Pinton, Paolo, additional, Campanella, Michelangelo, additional, and Piacentini, Mauro, additional

Published
2018
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11. Mitochondria form contact sites with the nucleus to couple pro-survival retrograde response

Author

Desai, Radha, primary, East, Daniel A, additional, Hardy, Liana, additional, Crosby, James, additional, Rigon, Manuel, additional, Faccenda, Danilo, additional, Alvarez, María Soledad, additional, Singh, Aarti, additional, Mainenti, Marta, additional, Hussey, Laura Kuhlman, additional, Bentham, Robert, additional, Szabadkai, Gyorgy, additional, Zappulli, Valentina, additional, Dhoot, Gurtej, additional, Romano, Lisa E, additional, Dong, Xia, additional, Coppens, Isabelle, additional, Hamacher-Brady, Anne, additional, Chapple, J Paul, additional, Abeti, Rosella, additional, Fleck, Roland A., additional, Vizcay-Barrena, Gema, additional, Smith, Kenneth, additional, and Campanella, Michelangelo, additional

Published
2018
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14. ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism

Author

Desai, Radha, primary, Frazier, Ann E., additional, Durigon, Romina, additional, Patel, Harshil, additional, Jones, Aleck W., additional, Dalla Rosa, Ilaria, additional, Lake, Nicole J., additional, Compton, Alison G., additional, Mountford, Hayley S., additional, Tucker, Elena J., additional, Mitchell, Alice L. R., additional, Jackson, Deborah, additional, Sesay, Abdul, additional, Di Re, Miriam, additional, van den Heuvel, Lambert P., additional, Burke, Derek, additional, Francis, David, additional, Lunke, Sebastian, additional, McGillivray, George, additional, Mandelstam, Simone, additional, Mochel, Fanny, additional, Keren, Boris, additional, Jardel, Claude, additional, Turner, Anne M., additional, Ian Andrews, P., additional, Smeitink, Jan, additional, Spelbrink, Johannes N., additional, Heales, Simon J., additional, Kohda, Masakazu, additional, Ohtake, Akira, additional, Murayama, Kei, additional, Okazaki, Yasushi, additional, Lombès, Anne, additional, Holt, Ian J., additional, Thorburn, David R., additional, and Spinazzola, Antonella, additional

Published
2017
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18. Transglutaminase Type 2 Regulates ER-Mitochondria Contact Sites by Interacting with GRP75.

Author

D'Eletto, Manuela, Rossin, Federica, Occhigrossi, Luca, Farrace, Maria Grazia, Faccenda, Danilo, Desai, Radha, Marchi, Saverio, Refolo, Giulia, Falasca, Laura, Antonioli, Manuela, Ciccosanti, Fabiola, Fimia, Gian Maria, Pinton, Paolo, Campanella, Michelangelo, and Piacentini, Mauro

Abstract

Summary Transglutaminase type 2 (TG2) is a multifunctional enzyme that plays a key role in mitochondria homeostasis under stressful cellular conditions. TG2 interactome analysis reveals an enzyme interaction with GRP75 (glucose-regulated protein 75). GRP75 localizes in mitochondria-associated membranes (MAMs) and acts as a bridging molecule between the two organelles by assembling the IP3R-GRP75-VDAC complex, which is involved in the transport of Ca2+ from the endoplasmic reticulum (ER) to mitochondria. We demonstrate that the TG2 and GRP75 interaction occurs in MAMs. The absence of the TG2-GRP75 interaction leads to an increase of the interaction between IP3R-3 and GRP75; a decrease of the number of ER-mitochondria contact sites; an impairment of the ER-mitochondrial Ca2+ flux; and an altered profile of the MAM proteome. These findings indicate TG2 is a key regulatory element of the MAMs. Graphical Abstract Highlights • TG2 interacts with GRP75 in mitochondria-associated membranes (MAMs) • TG2 influences the number of ER-mitochondria contact sites • TG2 regulates the interaction between IP3R3 and GRP75 • TG2 controls ER-mitochondrial Ca2+ flux and protein expression in MAMs TG2 is an enzyme that plays a key role in mitochondria homeostasis. D'eletto et al. found that TG2 interacts with GRP75, a protein localized in mitochondria-associated membranes (MAMs). TG2 regulates the number of ER-mitochondria contact sites and Ca2+ flux, suggesting a key regulatory role in MAMs. [ABSTRACT FROM AUTHOR]

Published
2018
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