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

Ilari Pulli, C Löf, T Blom, Muhammad Yasir Asghar, Taru Lassila, N Bäck, Kai-Lan Lin, JH Nyström, Kati Kemppainen, Diana Toivola, E Dufour, A Sanz, Helen Cooper, JB Parys, Kid Törnquist

Tutkimustuotos: LehtiartikkeliArtikkeliTieteellinenvertaisarvioitu

3 Sitaatiot (Scopus)

Abstrakti

Sphingosine kinase 1 (SKI) converts sphingosine to the bioactive lipid sphingosine 1-phosphate (SIP). SW binds to G-protein-coupled receptors (S1PR(1-5)) 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 SKI augments agonist-induced Ca2+ release from the ER resulting in increased mitochondria] 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.
AlkuperäiskieliEi tiedossa
Sivut1475–1486
Sivumäärä12
JulkaisuBiochimica et Biophysica Acta (BBA) - Molecular Cell Research
Vuosikerta1866
Numero9
DOI - pysyväislinkit
TilaJulkaistu - 2019
OKM-julkaisutyyppiA1 Julkaistu artikkeli, soviteltu

Keywords

  • Sphingosine kinase
  • Mitofusin-2
  • Mitochondria
  • Endoplasmic reticulum
  • Sphingosine 1-phosphate

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