Sphingosine kinase 1 overexpression induces MFN2 fragmentation and alters mitochondrial matrix Ca2+ handling in HeLa cells

Pulli, I. et al. (2019) Sphingosine kinase 1 overexpression induces MFN2 fragmentation and alters mitochondrial matrix Ca2+ handling in HeLa cells. Biochimica et Biophysica Acta: Molecular Cell Research, 1866(9), pp. 1475-1486. (doi:10.1016/j.bbamcr.2019.06.006) (PMID:31220477)

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Abstract

Sphingosine kinase 1 (SK1) converts sphingosine to the bioactive lipid sphingosine 1-phosphate (S1P). S1P binds to G-protein-coupled receptors (S1PR1–5) to regulate cellular events, including Ca2+ signaling. The SK1/S1P axis and Ca2+ signaling both play important roles in health and disease. In this respect, Ca2+ microdomains at the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are of importance in oncogenesis. Mitofusin 2 (MFN2) modulates ER-mitochondria contacts, and dysregulation of MFN2 is associated with malignancies. We show that overexpression of SK1 augments agonist-induced Ca2+ release from the ER resulting in increased mitochondrial matrix Ca2+. Also, overexpression of SK1 induces MFN2 fragmentation, likely through increased calpain activity. Further, expressing putative calpain-cleaved MFN2 N- and C-terminal fragments increases mitochondrial matrix Ca2+ during agonist stimulation, mimicking the SK1 overexpression in cells. Moreover, SK1 overexpression enhances cellular respiration and cell migration. Thus, SK1 regulates MFN2 fragmentation resulting in increased mitochondrial Ca2+ and downstream cellular effects.

Item Type:Articles
Additional Information:I.P. received funding from the following foundations: Svenska Kulturfonden, the Magnus Ehrnrooths stiftelse, Finsk-Norska medicinska stiftelsen, Tor, Joe och Pentti Borgs Minnesfond, Oscar Öflunds stiftelse, Waldemar Von Frenckells stiftelse, K. Albin Johanssons stiftelse and Ida Montins stiftelse. J.H.N. was supported by Svenska Kulturfonden and the Otto A. Malm Foundation. D.M.T. received funding from the Sigrid Juséliuksen Säätiö and from the Novo Nordisk Foundation. K.T. was supported by the Sigrid Juséliuksen Säätiö and the Liv och Hälsa Foundation.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Sanz Montero, Professor Alberto
Authors: Pulli, I., Löf, C., Blom, T., Asghar, M.Y., Lassila, T., Bäck, N., Lin, K.-L., Nyström, J.H., Kemppainen, K., Toivola, D.M., Dufour, E., Sanz, A., Cooper, H.M., Parys, J.B., and Törnquist, K.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Biochimica et Biophysica Acta: Molecular Cell Research
Publisher:Elsevier
ISSN:0167-4889
ISSN (Online):1879-2596
Published Online:17 June 2019

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