Enhanced inter-compartmental Ca2+ flux modulates mitochondrial metabolism and apoptotic threshold during aging
Corina T. Madreiter-Sokolowski,
Markus Waldeck-Weiermair,
Marie-Pierre Bourguignon,
Nicole Villeneuve,
Benjamin Gottschalk,
Christiane Klec,
Sarah Stryeck,
Snjezana Radulovic,
Warisara Parichatikanond,
Saša Frank,
Tobias Madl,
Roland Malli,
Wolfgang F. Graier
Affiliations
Corina T. Madreiter-Sokolowski
Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010 Graz, Austria; Department of Health Sciences and Technology, ETH Zurich, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland; Corresponding author at: Department of Health Sciences and Technology, ETH Zurich, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland.
Markus Waldeck-Weiermair
Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010 Graz, Austria
Marie-Pierre Bourguignon
Servier Research Institute, Cardiovascular Unit, 11 rue des Moulineaux, 92150 Suresnes, France
Nicole Villeneuve
Servier Research Institute, Cardiovascular Unit, 11 rue des Moulineaux, 92150 Suresnes, France
Benjamin Gottschalk
Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010 Graz, Austria
Christiane Klec
Division of Oncology, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria
Sarah Stryeck
Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010 Graz, Austria
Snjezana Radulovic
Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010 Graz, Austria
Warisara Parichatikanond
Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand
Saša Frank
Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010 Graz, Austria
Tobias Madl
Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010 Graz, Austria
Roland Malli
Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010 Graz, Austria; BioTechMed, Graz, Austria
Wolfgang F. Graier
Molecular Biology and Biochemistry, Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010 Graz, Austria; BioTechMed, Graz, Austria; Corresponding author at: Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, Neue Stiftingtalstraße 6/6, 8010 Graz, Austria.
Background: Senescence is characterized by a gradual decline in cellular functions, including changes in energy homeostasis and decreased proliferation activity. As cellular power plants, contributors to signal transduction, sources of reactive oxygen species (ROS) and executors of programmed cell death, mitochondria are in a unique position to affect aging-associated processes of cellular decline. Notably, metabolic activation of mitochondria is tightly linked to Ca2+ due to the Ca2+ -dependency of several enzymes in the Krebs cycle, however, overload of mitochondria with Ca2+ triggers cell death pathways. Consequently, a machinery of proteins tightly controls mitochondrial Ca2+ homeostasis as well as the exchange of Ca2+ between the different cellular compartments, including Ca2+ flux between mitochondria and the endoplasmic reticulum (ER). Methods: In this study, we investigated age-related changes in mitochondrial Ca2+ homeostasis, mitochondrial-ER linkage and the activity of the main ROS production site, the mitochondrial respiration chain, in an in vitro aging model based on porcine aortic endothelial cells (PAECs), using high-resolution live cell imaging, proteomics and various molecular biological methods. Results: We describe that in aged endothelial cells, increased ER-mitochondrial Ca2+ crosstalk occurs due to enhanced ER-mitochondrial tethering. The close functional inter-organelle linkage increases mitochondrial Ca2+ uptake and thereby the activity of the mitochondrial respiration, but also makes senescent cells more vulnerable to mitochondrial Ca2+-overload-induced cell death. Moreover, we identified the senolytic properties of the polyphenol resveratrol, triggering cell death via mitochondrial Ca2+ overload exclusively in senescent cells. Conclusion: By unveiling aging-related changes in the inter-organelle tethering and Ca2+ communications we have advanced the understanding of endothelial aging and highlighted a potential basis to develop drugs specifically targeting senescent cells. Keywords: Mitochondria, Endoplasmic reticulum, Calcium signaling, ER-mitochondrial coupling, Vascular aging