TRPC3 shapes the ER-mitochondria Ca2+ transfer characterizing tumour-promoting senescence
Valerio Farfariello
(1)
,
Dmitri Gordienko
(1)
,
Lina Mesilmany
(1)
,
Yasmine Touil
(2)
,
Emmanuelle Germain
(1)
,
Ingrid Fliniaux
(1)
,
Emilie Desruelles
(1)
,
Dimitra Gkika
(1)
,
Morad Roudbaraki
(1)
,
George Shapovalov
(1)
,
Lucile Noyer
(3)
,
Mathilde Lebas
(1)
,
Laurent Allart
(1)
,
Nathalie Zienthal-Gelus
(1)
,
Oksana Iamshanova
(4)
,
Franck Bonardi
(5)
,
Martin Figeac
(5)
,
William Laine
(2)
,
Jerome Kluza
(2)
,
Philippe Marchetti
(2)
,
Bruno Quesnel
(2)
,
Daniel Metzger
(6)
,
David Bernard
(7)
,
Jan Parys
(8)
,
Loïc Lemonnier
(1)
,
Natalia Prevarskaya
(1)
1
PHYCELL -
Laboratoire de Physiologie Cellulaire : Canaux ioniques, inflammation et cancer - U 1003
2 CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277
3 NYU Langone Medical Center - New York University Langone Medical Center
4 Institute of Biochemistry and Molecular Medicine, University of Bern
5 Institut de Pathologie, Centre de Biologie Pathologie Génétique, CS 70001, CHRU de Lille,
6 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
7 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
8 KU Leuven - Catholic University of Leuven - Katholieke Universiteit Leuven
2 CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277
3 NYU Langone Medical Center - New York University Langone Medical Center
4 Institute of Biochemistry and Molecular Medicine, University of Bern
5 Institut de Pathologie, Centre de Biologie Pathologie Génétique, CS 70001, CHRU de Lille,
6 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
7 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
8 KU Leuven - Catholic University of Leuven - Katholieke Universiteit Leuven
Valerio Farfariello
- Function : Author
- PersonId : 792311
- ORCID : 0000-0003-3918-0793
Lina Mesilmany
- Function : Author
- PersonId : 807304
- ORCID : 0000-0003-2930-115X
Yasmine Touil
- Function : Author
- PersonId : 772465
- ORCID : 0000-0002-2286-960X
Dimitra Gkika
- Function : Author
- PersonId : 1121984
- IdHAL : dimitra-gkika
Lucile Noyer
- Function : Author
- PersonId : 799833
- ORCID : 0000-0002-1369-684X
- IdRef : 242692885
Martin Figeac
- Function : Author
- PersonId : 762658
- ORCID : 0000-0001-8523-3708
- IdRef : 084528893
Jerome Kluza
- Function : Author
- PersonId : 21087
- IdHAL : jerome-kluza
- ORCID : 0000-0002-7346-1305
- IdRef : 175114935
Bruno Quesnel
- Function : Author
- PersonId : 767595
- ORCID : 0000-0002-6563-2709
- IdRef : 059849010
Daniel Metzger
- Function : Author
- PersonId : 180398
- IdHAL : daniel-metzger
- ORCID : 0000-0002-5555-046X
- IdRef : 086804901
David Bernard
- Function : Author
- PersonId : 178230
- IdHAL : david-bernard
- ORCID : 0000-0002-1557-2074
- IdRef : 060763639
Jan Parys
- Function : Author
- PersonId : 765601
- ORCID : 0000-0002-3591-4967
Loïc Lemonnier
- Function : Author
- PersonId : 757788
- ORCID : 0000-0001-6200-5382
- IdRef : 079563805
Natalia Prevarskaya
- Function : Author
- PersonId : 757787
- ORCID : 0000-0003-0316-197X
- IdRef : 134007840
Abstract
Abstract Cellular senescence is implicated in a great number of diseases including cancer. Although alterations in mitochondrial metabolism were reported as senescence drivers, the underlying mechanisms remain elusive. We report the mechanism altering mitochondrial function and OXPHOS in stress-induced senescent fibroblasts. We demonstrate that TRPC3 protein, acting as a controller of mitochondrial Ca 2+ load via negative regulation of IP 3 receptor-mediated Ca 2+ release, is down regulated in senescence regardless of the type of senescence inducer. This remodelling promotes cytosolic/mitochondrial Ca 2+ oscillations and elevates mitochondrial Ca 2+ load, mitochondrial oxygen consumption rate and oxidative phosphorylation. Re-expression of TRPC3 in senescent cells diminishes mitochondrial Ca 2+ load and promotes escape from OIS-induced senescence. Cellular senescence evoked by TRPC3 downregulation in stromal cells displays a proinflammatory and tumour-promoting secretome that encourages cancer epithelial cell proliferation and tumour growth in vivo. Altogether, our results unravel the mechanism contributing to pro-tumour behaviour of senescent cells.