Dual function of NME4/nucleoside diphosphate kinase D in bioenergetics and signaling death decisions

Orateur : Uwe SCHLATTNER (Univ. Grenoble Alpes and Inserm, LBFA U1055, Grenoble, France)

Several mitochondrial proteins have dual functions in bioenergetics and death signaling. We have shown that this is also the case for the major mitochondrial isoform of the NME/nucleoside diphosphate kinase (NDPK) family, called NME4, NM23-H4 or NDPK-D (1,2). The phosphotransfer activity of NME4 locally regenerates GTP for fueling the dynamin-related GTPase OPA1, a mechanism involving nucleotide channeling (3,4). This will affect OPA1 functions in mitochondrial shape and fusion dynamics. In addition, NME4 has transmembrane lipid transfer activity that is able to externalize cardiolipin (CL) from the inner membrane to the mitochondrial surface, following either mitophagic (5) or apoptotic triggers (6). This CL transfer relies on NME4/CL interaction, CL-dependent crosslinking of inner and outer mitochondrial membranes by the symmetrical, hexameric NME4 structure, and a putative NME4-based CL transfer pathway. Externalized CL then serves as an “eat me” signal for mitophagy by recruiting LC3-exposing autophagosomes (7), or in form of oxidized CL as a scaffold for recruiting and functionally altering different pro-apoptotic proteins. One factor inducing NME4-assisted CL transfer seems to be the loss of NME4/OPA1 complexes (5), possibly triggered by the known proteolytic cleavage of OPA1 after collapse of the inner membrane potential.

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