Corina T. Madreiter‐Sokolowski

Medical University of Graz

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Wolfgang F. Graier

Medical University of Graz

Roland Malli

Medical University of Graz

Benjamin Gottschalk

Medical University of Graz

Markus Waldeck‐Weiermair

Medical University of Graz

René Rost

Medical University of Graz

Christiane Klec

Medical University of Graz

Dagmar Kratky

Medical University of Graz

Tobias Madl

Medical University of Graz

Emrah Eroğlu

Istanbul Medipol University

Warisara Parichatikanond

Mahidol University

Cooperative Institutions

Medical University of Graz

134

University of Graz

BioTechMed-Graz

Graz University of Technology

Medical University of Vienna

Harvard University

Universität Innsbruck

Inserm

Father Muller Medical College Hospital

University of Montana

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Intact mitochondrial Ca 2+ uniport is essential for agonist-induced activation of endothelial nitric oxide synthase (eNOS)

Free Radical Biology and Medicine (2016)

Suphachai Charoensin Emrah Eroğlu Marissa Opelt Helmut Bischof Corina T. Madreiter‐Sokolowski

Mitochondrial Ca2+ uptake regulates diverse endothelial cell functions and has also been related to nitric oxide (NO•) production. However, it is not entirely clear if the organelles support or counteract NO• biosynthesis by taking up Ca2+. The objective of this study was to verify whether or not mitochondrial Ca2+ uptake influences Ca2+-triggered NO• generation by endothelial NO• synthase (eNOS) in an immortalized endothelial cell line (EA.hy926), respective primary human umbilical vein endothelial cells (HUVECs) and eNOS-RFP (red fluorescent protein) expressing human embryonic kidney (HEK293) cells. We used novel genetically encoded fluorescent NO• probes, the geNOps, and Ca2+ sensors to monitor single cell NO• and Ca2+ dynamics upon cell treatment with ATP, an inositol 1,4,5-trisphosphate (IP3)-generating agonist. Mitochondrial Ca2+ uptake was specifically manipulated by siRNA-mediated knock-down of recently identified key components of the mitochondrial Ca2+ uniporter machinery. In endothelial cells and the eNOS-RFP expressing HEK293 cells we show that reduced mitochondrial Ca2+ uptake upon the knock-down of the mitochondrial calcium uniporter (MCU) protein and the essential MCU regulator (EMRE) yield considerable attenuation of the Ca2+-triggered NO• increase independently of global cytosolic Ca2+ signals. The knock-down of mitochondrial calcium uptake 1 (MICU1), a gatekeeper of the MCU, increased both mitochondrial Ca2+ sequestration and Ca2+-induced NO• signals. The positive correlation between mitochondrial Ca2+ elevation and NO• production was independent of eNOS phosphorylation at serine1177. Our findings emphasize that manipulating mitochondrial Ca2+ uptake may represent a novel strategy to control eNOS-mediated NO• production.

Uniporter

HEK 293 cells

Endothelial NOS

10.1016/j.freeradbiomed.2016.11.049

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Citations (31)

Sigma-1 Receptor Promotes Mitochondrial Bioenergetics by Orchestrating ER Ca2+ Leak during Early ER Stress

Metabolites (2021)

Zhanat Koshenov Furkan E. Oflaz Martin Hirtl Johannes Pilic Olaf A. Bachkoenig

The endoplasmic reticulum (ER) is a complex, multifunctional organelle of eukaryotic cells and responsible for the trafficking and processing of nearly 30% of all human proteins. Any disturbance to these processes can cause ER stress, which initiates an adaptive mechanism called unfolded protein response (UPR) to restore ER functions and homeostasis. Mitochondrial ATP production is necessary to meet the high energy demand of the UPR, while the molecular mechanisms of ER to mitochondria crosstalk under such stress conditions remain mainly enigmatic. Thus, better understanding the regulation of mitochondrial bioenergetics during ER stress is essential to combat many pathologies involving ER stress, the UPR, and mitochondria. This article investigates the role of Sigma-1 Receptor (S1R), an ER chaperone, has in enhancing mitochondrial bioenergetics during early ER stress using human neuroblastoma cell lines. Our results show that inducing ER stress with tunicamycin, a known ER stressor, greatly enhances mitochondrial bioenergetics in a time- and S1R-dependent manner. This is achieved by enhanced ER Ca2+ leak directed towards mitochondria by S1R during the early phase of ER stress. Our data point to the importance of S1R in promoting mitochondrial bioenergetics and maintaining balanced H2O2 metabolism during early ER stress.

Sigma-1 Receptor

Bioenergetics

Crosstalk

SERCA

10.3390/metabo11070422

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Citations (19)

Targeting cellular senescence based on interorganelle communication, multilevel proteostasis, and metabolic control

FEBS Journal (2020)

Maria Cavinato Corina T. Madreiter‐Sokolowski Sabrina Büttner Markus Schosserer Werner Zwerschke

Cellular senescence, a stable cell division arrest caused by severe damage and stress, is a hallmark of aging in vertebrates including humans. With progressing age, senescent cells accumulate in a variety of mammalian tissues, where they contribute to tissue aging, identifying cellular senescence as a major target to delay or prevent aging. There is an increasing demand for the discovery of new classes of small molecules that would either avoid or postpone cellular senescence by selectively eliminating senescent cells from the body (i.e., 'senolytics') or inactivating/switching damage-inducing properties of senescent cells (i.e., 'senostatics/senomorphics'), such as the senescence-associated secretory phenotype. Whereas compounds with senolytic or senostatic activity have already been described, their efficacy and specificity has not been fully established for clinical use yet. Here, we review mechanisms of senescence that are related to mitochondria and their interorganelle communication, and the involvement of proteostasis networks and metabolic control in the senescent phenotype. These cellular functions are associated with cellular senescence in in vitro and in vivo models but have not been fully exploited for the search of new compounds to counteract senescence yet. Therefore, we explore possibilities to target these mechanisms as new opportunities to selectively eliminate and/or disable senescent cells with the aim of tissue rejuvenation. We assume that this research will provide new compounds from the chemical space which act as mimetics of caloric restriction, modulators of calcium signaling and mitochondrial physiology, or as proteostasis optimizers, bearing the potential to counteract cellular senescence, thereby allowing healthy aging.

Proteostasis

Senescence

Cellular model

Cellular senescence

10.1111/febs.15631

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Citations (23)

BRET-based assay to specifically monitor β2AR/GRK2 interaction and β-arrestin2 conformational change upon βAR stimulation

Methods in cell biology (2021)

Warisara Parichatikanond Ei Thet Htar Kyaw Corina T. Madreiter‐Sokolowski Supachoke Mangmool

Arrestin

Conformational change

10.1016/bs.mcb.2021.06.005

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Citations (0)

Monoglyceride lipase regulates endocannabinoid tone and atherosclerotic plaque structure in apolipoprotein E-deficient mice

Atherosclerosis (2016)

Nemanja Vujić Stefanie Schlager Thomas O. Eichmann Madeleine Goeritzer Corina T. Madreiter‐Sokolowski

2-Arachidonoylglycerol

Monoglyceride

Diacylglycerol lipase

10.1016/j.atherosclerosis.2016.07.086

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Development of novel FP-based probes for live-cell imaging of nitric oxide dynamics

Nature Communications (2016)

Emrah Eroğlu Benjamin Gottschalk Suphachai Charoensin Sandra Blaß Helmut Bischof

Abstract Nitric oxide ("Equation missing") is a free radical with a wide range of biological effects, but practically impossible to visualize in single cells. Here we report the development of novel multicoloured fluorescent quenching-based "Equation missing" probes by fusing a bacteria-derived "Equation missing"-binding domain close to distinct fluorescent protein variants. These genetically encoded "Equation missing" probes, referred to as geNOps, provide a selective, specific and real-time read-out of cellular "Equation missing" dynamics and, hence, open a new era of "Equation missing" bioimaging. The combination of geNOps with a Ca 2+ sensor allowed us to visualize "Equation missing" and Ca 2+ signals simultaneously in single endothelial cells. Moreover, targeting of the "Equation missing" probes was used to detect "Equation missing" signals within mitochondria. The geNOps are useful new tools to further investigate and understand the complex patterns of "Equation missing" signalling on the single (sub)cellular level.

Dynamics

10.1038/ncomms10623

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Citations (103)

Calcium Sensors ALG-2 And Peflin Bind ER Exit Sites In Alternate States To Modulate Secretion In Response To Calcium Signaling

bioRxiv (Cold Spring Harbor Laboratory) (2020)

John Sargeant Tucker Costain Corina T. Madreiter‐Sokolowski David E. Gordon Andrew A. Peden

Penta EF-hand (PEF) proteins apoptosis-linked gene 2 (ALG-2) and peflin are cytoplasmic Ca2+ sensors for which physiological roles are still emerging. Here we demonstrate that adjustment of the ALG-2:peflin expression ratio can modulate basal ER export rates up or down by 107% of the basal rate. Through their ALG-2 subunit, ALG-2-peflin hetero-oligomers are shown to bind ERES and inhibit ER export of multiple cargo types, including collagen I, while ALG-2 by itself binds ERES to stimulate cargo sorting and ER export. During sustained Ca2+ signaling, peflin and ALG-2 are demonstrated to sharply lower ER export rates by 40% in a novel secretory response to demanding physiological conditions. However, in highly Ca2+-stressed cells, peflin9s suppressive role appears to promote pro-apoptotic unfolded protein response (UPR) signaling, indicating that the regulation is not necessarily pro-survival. Thus, regulation of secretion by PEF protein sub-complex binding to ERES in response to Ca2+ signals impacts key cellular decision processes relevant to aging, neurodegeneration and diabetes.

Calcium Signaling

Basal (medicine)

Source

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Citations (1)

Critical role of the peroxisomal protein PEX16 in white adipocyte development and lipid homeostasis

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids (2016)

Dina Hofer Ariane Pessentheiner Helmut Josef Pelzmann Stefanie Schlager Corina T. Madreiter‐Sokolowski

The importance of peroxisomes for adipocyte function is poorly understood. Herein, we provide insights into the critical role of peroxin 16 (PEX16)-mediated peroxisome biogenesis in adipocyte development and lipid metabolism. Pex16 is highly expressed in adipose tissues and upregulated during adipogenesis of murine and human cells. We demonstrate that Pex16 is a target gene of the adipogenesis "master-regulator" PPARγ. Stable silencing of Pex16 in 3T3-L1 cells strongly reduced the number of peroxisomes while mitochondrial number was unaffected. Concomitantly, peroxisomal fatty acid (FA) oxidation was reduced, thereby causing accumulation of long- and very long-chain (polyunsaturated) FAs and reduction of odd-chain FAs. Further, Pex16-silencing decreased cellular oxygen consumption and increased FA release. Additionally, silencing of Pex16 impaired adipocyte differentiation, lipogenic and adipogenic marker gene expression, and cellular triglyceride stores. Addition of PPARγ agonist rosiglitazone and peroxisome-related lipid species to Pex16-silenced 3T3-L1 cells rescued adipogenesis. These data provide evidence that PEX16 is required for peroxisome biogenesis and highlights the relevance of peroxisomes for adipogenesis and adipocyte lipid metabolism.

Lipid droplet

10.1016/j.bbalip.2016.12.009

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Citations (27)

EGCG Promotes FUS Condensate Formation in a Methylation-Dependent Manner

Cells (2022)

Aneta J. Lenard Qishun Zhou Corina T. Madreiter‐Sokolowski Benjamin Bourgeois Hermann Habacher

Millions of people worldwide are affected by neurodegenerative diseases (NDs), and to date, no effective treatment has been reported. The hallmark of these diseases is the formation of pathological aggregates and fibrils in neural cells. Many studies have reported that catechins, polyphenolic compounds found in a variety of plants, can directly interact with amyloidogenic proteins, prevent the formation of toxic aggregates, and in turn play neuroprotective roles. Besides harboring amyloidogenic domains, several proteins involved in NDs possess arginine-glycine/arginine-glycine-glycine (RG/RGG) regions that contribute to the formation of protein condensates. Here, we aimed to assess whether epigallocatechin gallate (EGCG) can play a role in neuroprotection via direct interaction with such RG/RGG regions. We show that EGCG directly binds to the RG/RGG region of fused in sarcoma (FUS) and that arginine methylation enhances this interaction. Unexpectedly, we found that low micromolar amounts of EGCG were sufficient to restore RNA-dependent condensate formation of methylated FUS, whereas, in the absence of EGCG, no phase separation could be observed. Our data provide new mechanistic roles of EGCG in the regulation of phase separation of RG/RGG-containing proteins, which will promote understanding of the intricate function of EGCG in cells.

10.3390/cells11040592

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Myeloperoxidase and Septic Conditions Disrupt Sphingolipid Homeostasis in Murine Brain Capillaries In Vivo and Immortalized Human Brain Endothelial Cells In Vitro

International Journal of Molecular Sciences (2020)

Madeleine Goeritzer Eva Bernhart Ioanna Plastira Helga Reicher Christina Leopold

During inflammation, activated leukocytes release cytotoxic mediators that compromise blood–brain barrier (BBB) function. Under inflammatory conditions, myeloperoxidase (MPO) is critically involved in inflicting BBB damage. We used genetic and pharmacological approaches to investigate whether MPO induces aberrant lipid homeostasis at the BBB in a murine endotoxemia model. To corroborate findings in a human system we studied the impact of sera from sepsis and non-sepsis patients on brain endothelial cells (hCMEC/D3). In response to endotoxin, the fatty acid, ceramide, and sphingomyelin content of isolated mouse brain capillaries dropped and barrier dysfunction occurred. In mice, genetic deficiency or pharmacological inhibition of MPO abolished these alterations. Studies in metabolic cages revealed increased physical activity and less pronounced sickness behavior of MPO−/− compared to wild-type mice in response to sepsis. In hCMEC/D3 cells, exogenous tumor necrosis factor α (TNFα) potently regulated gene expression of pro-inflammatory cytokines and a set of genes involved in sphingolipid (SL) homeostasis. Notably, treatment of hCMEC/D3 cells with sera from septic patients reduced cellular ceramide concentrations and induced barrier and mitochondrial dysfunction. In summary, our in vivo and in vitro data revealed that inflammatory mediators including MPO, TNFα induce dysfunctional SL homeostasis in brain endothelial cells. Genetic and pharmacological inhibition of MPO attenuated endotoxin-induced alterations in SL homeostasis in vivo, highlighting the potential role of MPO as drug target to treat inflammation-induced brain dysfunction.

Acid sphingomyelinase

Sphingolipid

Homeostasis

Endothelial Dysfunction

10.3390/ijms21031143

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Citations (12)