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

A1 Originalartikel i en vetenskaplig tidskrift (referentgranskad)

Interna författare/redaktörer

Publikationens författare: Pulli I, Löf C, Blom T, Asghar MY, Lassila T, Bäck N, Lin KL, Nyström JH, Kemppainen K, Toivola DM, Dufour E, Sanz A, Cooper HM, Parys JB, Törnquist K
Förläggare: ELSEVIER
Publiceringsår: 2019
Tidskrift: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
Tidskriftsakronym: BBA-MOL CELL RES
Volym: 1866
Nummer: 9
Artikelns första sida, sidnummer: 1475
Artikelns sista sida, sidnummer: 1486
Antal sidor: 12
ISSN: 0167-4889


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.


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

Senast uppdaterad 2020-02-04 vid 05:43