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Featured researches published by Niko Kivinen.


PLOS ONE | 2013

Autophagy Activation Clears ELAVL1/HuR-Mediated Accumulation of SQSTM1/p62 during Proteasomal Inhibition in Human Retinal Pigment Epithelial Cells

Johanna Viiri; Marialaura Amadio; Nicoletta Marchesi; Juha M.T. Hyttinen; Niko Kivinen; Reijo Sironen; Kirsi Rilla; Saeed Akhtar; Alessandro Provenzani; Vito Giuseppe D'Agostino; Stefano Govoni; Alessia Pascale; Hansjürgen T. Agostini; Goran Petrovski; Antero Salminen; Kai Kaarniranta

Age-related macular degeneration (AMD) is the most common reason of visual impairment in the elderly in the Western countries. The degeneration of retinal pigment epithelial cells (RPE) causes secondarily adverse effects on neural retina leading to visual loss. The aging characteristics of the RPE involve lysosomal accumulation of lipofuscin and extracellular protein aggregates called “drusen”. Molecular mechanisms behind protein aggregations are weakly understood. There is intriguing evidence suggesting that protein SQSTM1/p62, together with autophagy, has a role in the pathology of different degenerative diseases. It appears that SQSTM1/p62 is a connecting link between autophagy and proteasome mediated proteolysis, and expressed strongly under the exposure to various oxidative stimuli and proteasomal inhibition. ELAVL1/HuR protein is a post-transcriptional factor, which acts mainly as a positive regulator of gene expression by binding to specific mRNAs whose corresponding proteins are fundamental for key cellular functions. We here show that, under proteasomal inhibitor MG-132, ELAVL1/HuR is up-regulated at both mRNA and protein levels, and that this protein binds and post-transcriptionally regulates SQSTM1/p62 mRNA in ARPE-19 cell line. Furthermore, we observed that proteasomal inhibition caused accumulation of SQSTM1/p62 bound irreversibly to perinuclear protein aggregates. The addition of the AMPK activator AICAR was pro-survival and promoted cleansing by autophagy of the former complex, but not of the ELAVL1/HuR accumulation, indeed suggesting that SQSTM1/p62 is decreased through autophagy-mediated degradation, while ELAVL1/HuR through the proteasomal pathway. Interestingly, when compared to human controls, AMD donor samples show strong SQSTM1/p62 rather than ELAVL1/HuR accumulation in the drusen rich macular area suggesting impaired autophagy in the pathology of AMD.


International Journal of Molecular Sciences | 2017

Autophagy regulates proteasome inhibitor-induced pigmentation in human embryonic stem cell-derived retinal pigment epithelial cells

Kati Juuti-Uusitalo; Ali Koskela; Niko Kivinen; Johanna Viiri; Juha M.T. Hyttinen; Mika Reinisalo; Arto Koistinen; Hannu Uusitalo; Debasish Sinha; Heli Skottman; Kai Kaarniranta

The impairment of autophagic and proteasomal cleansing together with changes in pigmentation has been documented in retinal pigment epithelial (RPE) cell degeneration. However, the function and co-operation of these mechanisms in melanosome-containing RPE cells is still unclear. We show that inhibition of proteasomal degradation with MG-132 or autophagy with bafilomycin A1 increased the accumulation of premelanosomes and autophagic structures in human embryonic stem cell (hESC)-derived RPE cells. Consequently, upregulation of the autophagy marker p62 (also known as sequestosome-1, SQSTM1) was confirmed in Western blot and perinuclear staining. Interestingly, cells treated with the adenosine monophosphatedependent protein kinase activator, AICAR (5-Aminoimidazole-4-carboxamide ribonucleotide), decreased the proteasome inhibitor-induced accumulation of premelanosomes, increased the amount of autophagosomes and eradicated the protein expression of p62 and LC3 (microtubule-associated protein 1A/1B-light chain 3). These results revealed that autophagic machinery is functional in hESC-RPE cells and may regulate cellular pigmentation with proteasomes.


Histology and Histopathology | 2015

A novel proteotoxic stress associated mechanism for macular corneal dystrophy

Kai Kaarniranta; Eszter Szalai; A Smedowski; Zoltán Hegyi; Niko Kivinen; Johanna Viiri; Bogumil Wowra; Dariusz Dobrowolski; László Módis; András Berta; Edward Wylegala; Szabolcs Felszeghy

Macular corneal dystrophy is a rare autosomal recessive eye disease affecting primarily the corneal stroma. Abnormal accumulation of proteoglycan aggregates has been observed intra- and extracellularly in the stromal layer. In addition to the stromal keratocytes and corneal lamellae, deposits are also present in the basal epithelial cells, endothelial cells and Descemets membrane. Misfolding of proteins has a tendency to gather into aggregating deposits. We studied interaction of molecular chaperones and proteasomal clearance in macular dystrophy human samples and in human corneal HCE-2 epithelial cells. Seven cases of macular corneal dystrophy and four normal corneal buttons collected during corneal transplantation were examined for their expression patterns of heat shock protein 70, ubiquitin protein conjugates and SQSTM1/p62. In response to proteasome inhibition the same proteins were analyzed by western blotting. Slit-lamp examination, in vivo confocal cornea microscopy and transmission electron microscopy were used for morphological analyses. Heat shock protein 70, ubiquitin protein conjugates and SQSTM1/p62 were upregulated in both the basal corneal epithelial cells and the stromal keratocytes in macular corneal dystrophy samples that coincided with an increased expression of the same molecules under proteasome inhibition in the HCE-2 cells in vitro. We propose a novel regulatory mechanism that connects the molecular chaperone and proteasomal clearance system in the pathogenesis of macular corneal dystrophy.


Redox biology | 2019

Loss of NRF-2 and PGC-1α genes leads to retinal pigment epithelium damage resembling dry age-related macular degeneration

Szabolcs Felszeghy; Johanna Viiri; Jussi J. Paterno; Juha M.T. Hyttinen; Ali Koskela; Mei Chen; Henri Leinonen; Heikki Tanila; Niko Kivinen; Arto Koistinen; Elisa Toropainen; Marialaura Amadio; A Smedowski; Mika Reinisalo; Mateusz Winiarczyk; Jerzy Mackiewicz; Maija Mutikainen; Anna Kaisa Ruotsalainen; Mikko I. Kettunen; Kimmo T. Jokivarsi; Debasish Sinha; Kati Kinnunen; Goran Petrovski; Janusz Blasiak; Geir Bjørkøy; Ari Koskelainen; Heli Skottman; Arto Urtti; Antero Salminen; Ram Kannan

Age-related macular degeneration (AMD) is a multi-factorial disease that is the leading cause of irreversible and severe vision loss in the developed countries. It has been suggested that the pathogenesis of dry AMD involves impaired protein degradation in retinal pigment epithelial cells (RPE). RPE cells are constantly exposed to oxidative stress that may lead to the accumulation of damaged cellular proteins, DNA and lipids and evoke tissue deterioration during the aging process. The ubiquitin-proteasome pathway and the lysosomal/autophagosomal pathway are the two major proteolytic systems in eukaryotic cells. NRF-2 (nuclear factor-erythroid 2-related factor-2) and PGC-1α (peroxisome proliferator-activated receptor gamma coactivator-1 alpha) are master transcription factors in the regulation of cellular detoxification. We investigated the role of NRF-2 and PGC-1α in the regulation of RPE cell structure and function by using global double knockout (dKO) mice. The NRF-2/PGC-1α dKO mice exhibited significant age-dependent RPE degeneration, accumulation of the oxidative stress marker, 4-HNE (4-hydroxynonenal), the endoplasmic reticulum stress markers GRP78 (glucose-regulated protein 78) and ATF4 (activating transcription factor 4), and damaged mitochondria. Moreover, levels of protein ubiquitination and autophagy markers p62/SQSTM1 (sequestosome 1), Beclin-1 and LC3B (microtubule associated protein 1 light chain 3 beta) were significantly increased together with the Iba-1 (ionized calcium binding adaptor molecule 1) mononuclear phagocyte marker and an enlargement of RPE size. These histopathological changes of RPE were accompanied by photoreceptor dysmorphology and vision loss as revealed by electroretinography. Consequently, these novel findings suggest that the NRF-2/PGC-1α dKO mouse is a valuable model for investigating the role of proteasomal and autophagy clearance in the RPE and in the development of dry AMD.


Biochimie | 2018

Fatty acids and oxidized lipoproteins contribute to autophagy and innate immunity responses upon the degeneration of retinal pigment epithelium and development of age-related macular degeneration

Kai Kaarniranta; Ali Koskela; Szabolcs Felszeghy; Niko Kivinen; Antero Salminen; Anu Kauppinen

Retinal pigment epithelium (RPE) damage is a primary sign in the development of age-related macular degeneration (AMD) the leading cause of blindness in western countries. RPE cells are exposed to chronic oxidative stress due to constant light exposure, active fatty acid metabolism and high oxygen consumption. RPE cells phagocytosize lipid rich photoreceptor outer segment (POS) which is regulated by circadian rhytmn. Docosahexaenoic acid is present in high quantity in POS and increases oxidative stress, while its metabolites have cytoprotective effects in RPE. During RPE aging, reactive oxygen species and oxidized lipoproteins are considered to be major causes of disturbed autophagy clearance that lead to chronic innate immunity response involved in NOD-Like, Toll-Like, Advanced Glycation End product Receptors (NLRP, TLR, RAGE, respectively), pentraxins and complement systems. We discuss role of fatty acids and lipoproteins in the degeneration of RPE and development of AMD.


Acta Ophthalmologica | 2018

The role of autophagy in age-related macular degeneration (AMD) - studies into the pathogenesis of AMD

Niko Kivinen

Age-related macular degeneration (AMD) is themajor reason for blindness and visual impairment in the developed countries. The prevalence of AMD is increasing due to the rise in life expectancy. There are estimations that the number of AMD patients will at least triple in the upcoming decades. About eight in 10 of AMD patients suffer from the untreatable dry form of AMD. The progression of wet AMD can be slowed downor in some cases even stoppedwith anti-vascular endothelial growth factor medications. Nonetheless, the pathogenesis of AMD has been a somewhat mysteryuntil recent discoveries. It seems that chronic oxidative stress evokes disturbances in proteasomal and autophagy clearance that secondarily leads to inflammation.


Acta Ophthalmologica | 2018

The role of autophagy in age-related macular degeneration

Niko Kivinen

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the developed countries. The prevalence of disease is expected to triple in the approaching decades. At the moment, only those cases which present choroidal neovascularization, a hallmark of wet AMD, are treatable with antiproliferative therapeutic agents. Unfortunately, these cases account for only 10–15% of all AMD patients, i.e. most patients are still without any treatment options. The key role in the development of AMD can be traced the degeneration of retinal pigment epithelium cells (RPE) which are the caretakers of photoreceptor rod and cones. The aim of the study was to clarify the role of autophagy in the pathogenesis of AMD. Ocular samples from knock-out mice and human cadavers were used in the experiments in conjunction with laboratory grown RPE-cell lines; samples were examined by modern cell and molecular biological techniques as well as immunohistochemical methods. Finally, a test series with collagen 18 total knock-out (Col18a1 / ) mice was conducted. The above methods were used to evaluate proteostasis of RPE in the mouse model. The levels of SQSTM1/p62 protein were elevated in macular areas of AMD cadaver samples; this was interpreted as evidence that a dysfunction of autophagy is involved in AMD pathogenesis. We also noted that the molecular chaperone, Hsp70, which has a strong cytoprotective capacity, evades autophagic clearance. The current standard-of-care for AMD has no effect on the activity of autophagy in RPE cells. An age-related insufficiency of proteostasis was observed together with RPE degeneration in Col18a1 / mice. We conclude that SQSTM1/p62 is a good marker for impaired autophagy. Furthermore, Hsp70 upregulation could be used as a therapeutic target against retinal pigment epithelium (RPE) degeneration and in the development novel treatments for AMD. Finally, Col18a1 / mice, which display AMD-like tissue alterations may represent a relevant animal model for impaired autophagy and AMD. National Library of Medicine Classification: WW 270, QU 375, QZ 140 Medical Subject Headings: Age-related Macular Degeneration; AMD pathophysiology; Autophagy; Animal model; Mouse model; Ocular disease; Blindness; Visual impairment Kivinen Niko Autophagian rooli silm€anpohjan ik€arappeumassa, tutkimuksia AMD:n patogeneesist€a It€a-Suomen yliopisto, terveystieteiden tiedekunta Publications of the University of Eastern Finland. Dissertations in Health Sciences Numero 400. 2017. 117 s. ISBN (print): 978-952-61-2413-1 ISBN (pdf): 978-952-61-2414-8 ISSN (print): 1798-5706 ISSN (pdf): 1798-5714 ISSN-L: 1798-5706


Archive | 2014

Hsp70 binds reversibly to proteasome inhibitor- induced protein aggregates and evades autophagic clearance in ARPE-19 cells

Niko Kivinen; Juha M.T. Hyttinen; Johanna Viiri; Jussi J. Paterno; Szabolcs Felszheghy; Anu Kauppinen; Antero Salminen; Kai Kaarniranta


Archive | 2014

Bevacizumab does not affect autophagy clearance during proteasomal inhibition in human retinal pigment epithelial cells

Niko Kivinen; Michaela Dithmer; Kati Kinnunen; Ralph Lucius; Johann Roider; Kai Kaarniranta; Alexa Klettner


Biogerontology | 2016

Absence of collagen XVIII in mice causes age-related insufficiency in retinal pigment epithelium proteostasis

Niko Kivinen; Szabolcs Felszeghy; Aino I. Kinnunen; Niko Setälä; Mari Aikio; Kati Kinnunen; Reijo Sironen; Taina Pihlajaniemi; Anu Kauppinen; Kai Kaarniranta

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Kai Kaarniranta

University of Eastern Finland

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Johanna Viiri

University of Eastern Finland

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Juha M.T. Hyttinen

University of Eastern Finland

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Anu Kauppinen

University of Eastern Finland

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Ali Koskela

University of Eastern Finland

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Antero Salminen

University of Eastern Finland

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Kati Kinnunen

University of Eastern Finland

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Arto Koistinen

University of Eastern Finland

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