Mitochondrial Nm23-H4/NDPK-D is Multifunctional: Intermembrane Cardiolipin Transfer Linked to Apoptosis - Université Grenoble Alpes
Poster De Conférence Année : 2013

Mitochondrial Nm23-H4/NDPK-D is Multifunctional: Intermembrane Cardiolipin Transfer Linked to Apoptosis

Résumé

Nm23-H4/NDPK-D forms symmetrical homohexameric complexes in the mitochondrial intermembrane space. The well established function of the enzyme is phosphotransfer activity as a nucleoside diphosphate kinase (NDPK), using mitochondrial ATP to regenerate nucleoside triphosphates. Nm23-H4 is further known to strongly bind in vitro to anionic phospholipids, mainly cardiolipin, and in vivo to inner mitochondrial membranes. We show here that such protein/lipid complexes inhibit NDPK activity but are necessary for Nm23-H4 to function in selective intermembrane lipid transfer. Nm23-H4-deficient HeLa cells expressing either wild-type Nm23-H4 or a membrane-binding deficient mutant were analyzed by membrane fractionation and LC-ESI-MS. Data revealed that wild-type Nm24-H4 increased cardiolipin content in the outer mitochondrial membrane as compared to mutant enzyme. This correlated with higher susceptibility of wild-type enzyme expressing cells to rotenone-induced apoptosis as seen by increased annexin V binding, elevated caspase 3/7 activity and stimulated release of cytochrome c into the cytosol. Molecular modeling of Nm23-H4 binding with cardiolipin reveals potential intermembrane transfer mechanisms. We propose that Nm23-H4 acts as a lipid-dependent mitochondrial switch with dual function, allowing either for phosphotransfer or for cardiolipin transfer, with a role in apoptotic signaling.

Dates et versions

hal-01955197 , version 1 (14-12-2018)

Identifiants

Citer

Uwe Schlattner, Malgorzata Tokarska-Schlattner, Sacnite Ramirez, Yulia Tyurina, Andrew Amoscato, et al.. Mitochondrial Nm23-H4/NDPK-D is Multifunctional: Intermembrane Cardiolipin Transfer Linked to Apoptosis. 57th Annual Meeting of the Biophysical Society, Feb 2013, Philadelphia, United States. 104 (2 suppl 1), pp.216a, Biophysical Journal. ⟨10.1016/j.bpj.2012.11.1222⟩. ⟨hal-01955197⟩
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