Enhanced Inter-compartmental Ca Flux Modulates Mitochondrial Metabolism and Apoptotic Threshold During Aging

Overview

Journal Redox Biol

Specialties Biology
Cell Biology
Endocrinology

Date 2018 Nov 21

PMID 30458321

Citations 32

Authors

Corina T Madreiter-Sokolowski

Markus Waldeck-Weiermair

Marie-Pierre Bourguignon

Nicole Villeneuve

Benjamin Gottschalk

Christiane Klec

Sarah Stryeck

Snjezana Radulovic

Warisara Parichatikanond

Sasa Frank

Tobias Madl

Roland Malli

Wolfgang F Graier

Affiliations

Soon will be listed here.

Abstract

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 Ca due to the Ca -dependency of several enzymes in the Krebs cycle, however, overload of mitochondria with Ca triggers cell death pathways. Consequently, a machinery of proteins tightly controls mitochondrial Ca homeostasis as well as the exchange of Ca between the different cellular compartments, including Ca flux between mitochondria and the endoplasmic reticulum (ER).

Methods: In this study, we investigated age-related changes in mitochondrial Ca 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 Ca crosstalk occurs due to enhanced ER-mitochondrial tethering. The close functional inter-organelle linkage increases mitochondrial Ca uptake and thereby the activity of the mitochondrial respiration, but also makes senescent cells more vulnerable to mitochondrial Ca-overload-induced cell death. Moreover, we identified the senolytic properties of the polyphenol resveratrol, triggering cell death via mitochondrial Ca overload exclusively in senescent cells.

Conclusion: By unveiling aging-related changes in the inter-organelle tethering and Ca communications we have advanced the understanding of endothelial aging and highlighted a potential basis to develop drugs specifically targeting senescent cells.

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References

Naghdi S, Waldeck-Weiermair M, Fertschai I, Poteser M, Graier W, Malli R . Mitochondrial Ca2+ uptake and not mitochondrial motility is required for STIM1-Orai1-dependent store-operated Ca2+ entry. J Cell Sci. 2010; 123(Pt 15):2553-64. DOI: 10.1242/jcs.070151. View

Zu Y, Liu L, Lee M, Xu C, Liang Y, Man R . SIRT1 promotes proliferation and prevents senescence through targeting LKB1 in primary porcine aortic endothelial cells. Circ Res. 2010; 106(8):1384-93. DOI: 10.1161/CIRCRESAHA.109.215483. View

Samanta K, Douglas S, Parekh A . Mitochondrial calcium uniporter MCU supports cytoplasmic Ca2+ oscillations, store-operated Ca2+ entry and Ca2+-dependent gene expression in response to receptor stimulation. PLoS One. 2014; 9(7):e101188. PMC: 4086884. DOI: 10.1371/journal.pone.0101188. View

Dieterle F, Ross A, Schlotterbeck G, Senn H . Probabilistic quotient normalization as robust method to account for dilution of complex biological mixtures. Application in 1H NMR metabonomics. Anal Chem. 2006; 78(13):4281-90. DOI: 10.1021/ac051632c. View

Fernandez-Sanz C, Ruiz-Meana M, Miro-Casas E, Nunez E, Castellano J, Loureiro M . Defective sarcoplasmic reticulum-mitochondria calcium exchange in aged mouse myocardium. Cell Death Dis. 2014; 5:e1573. PMC: 4454162. DOI: 10.1038/cddis.2014.526. View

Waldeck-Weiermair M, Alam M, Jadoon Khan M, Deak A, Vishnu N, Karsten F . Spatiotemporal correlations between cytosolic and mitochondrial Ca(2+) signals using a novel red-shifted mitochondrial targeted cameleon. PLoS One. 2012; 7(9):e45917. PMC: 3448721. DOI: 10.1371/journal.pone.0045917. View

Xu M, Pirtskhalava T, Farr J, Weigand B, Palmer A, Weivoda M . Senolytics improve physical function and increase lifespan in old age. Nat Med. 2018; 24(8):1246-1256. PMC: 6082705. DOI: 10.1038/s41591-018-0092-9. View

Pugh T, Conklin M, Evans T, Polewski M, Barbian H, Pass R . A shift in energy metabolism anticipates the onset of sarcopenia in rhesus monkeys. Aging Cell. 2013; 12(4):672-81. PMC: 3714309. DOI: 10.1111/acel.12091. View

Kirkland J, Tchkonia T, Zhu Y, Niedernhofer L, Robbins P . The Clinical Potential of Senolytic Drugs. J Am Geriatr Soc. 2017; 65(10):2297-2301. PMC: 5641223. DOI: 10.1111/jgs.14969. View

10.

Madreiter-Sokolowski C, Sokolowski A, Graier W . Dosis Facit Sanitatem-Concentration-Dependent Effects of Resveratrol on Mitochondria. Nutrients. 2017; 9(10). PMC: 5691733. DOI: 10.3390/nu9101117. View

11.

Kirkland J, Tchkonia T . Cellular Senescence: A Translational Perspective. EBioMedicine. 2017; 21:21-28. PMC: 5514381. DOI: 10.1016/j.ebiom.2017.04.013. View

12.

Martinez G, Duran-Aniotz C, Cabral-Miranda F, Vivar J, Hetz C . Endoplasmic reticulum proteostasis impairment in aging. Aging Cell. 2017; 16(4):615-623. PMC: 5506418. DOI: 10.1111/acel.12599. View

13.

Geng Y, Guan J, Xu X, Fu Y . Senescence-associated beta-galactosidase activity expression in aging hippocampal neurons. Biochem Biophys Res Commun. 2010; 396(4):866-9. DOI: 10.1016/j.bbrc.2010.05.011. View

14.

Lopez-Otin C, Blasco M, Partridge L, Serrano M, Kroemer G . The hallmarks of aging. Cell. 2013; 153(6):1194-217. PMC: 3836174. DOI: 10.1016/j.cell.2013.05.039. View

15.

Raturi A, Simmen T . Where the endoplasmic reticulum and the mitochondrion tie the knot: the mitochondria-associated membrane (MAM). Biochim Biophys Acta. 2012; 1833(1):213-24. DOI: 10.1016/j.bbamcr.2012.04.013. View

16.

Pitozzi V, Mocali A, Laurenzana A, Giannoni E, Cifola I, Battaglia C . Chronic resveratrol treatment ameliorates cell adhesion and mitigates the inflammatory phenotype in senescent human fibroblasts. J Gerontol A Biol Sci Med Sci. 2012; 68(4):371-81. DOI: 10.1093/gerona/gls183. View

17.

Calvo-Rodriguez M, Garcia-Durillo M, Villalobos C, Nunez L . In vitro aging promotes endoplasmic reticulum (ER)-mitochondria Ca cross talk and loss of store-operated Ca entry (SOCE) in rat hippocampal neurons. Biochim Biophys Acta. 2016; 1863(11):2637-2649. DOI: 10.1016/j.bbamcr.2016.08.001. View

18.

Munoz E, Hernandez-Morales M, Sobradillo D, Rocher A, Nunez L, Villalobos C . Intracellular Ca(2+) remodeling during the phenotypic journey of human coronary smooth muscle cells. Cell Calcium. 2013; 54(5):375-85. DOI: 10.1016/j.ceca.2013.08.006. View

19.

Miao L, St Clair D . Regulation of superoxide dismutase genes: implications in disease. Free Radic Biol Med. 2009; 47(4):344-56. PMC: 2731574. DOI: 10.1016/j.freeradbiomed.2009.05.018. View

20.

Brown M, Naidoo N . The endoplasmic reticulum stress response in aging and age-related diseases. Front Physiol. 2012; 3:263. PMC: 3429039. DOI: 10.3389/fphys.2012.00263. View