Mitochondrial NM23-H4/NDPK-D and OPA1: Partners in Shaping Mitochondria and Initiating Mitophagy?

Abstract

The well-established function of the mitochondrial intermembrane space protein NM23-H4/NDPK-D is phosphotransfer activity as a nucleoside diphosphate kinase (NDPK). However, recent data have revealed a second function in lipid signaling that triggers mitophagy, a critical process for cell homeostasis (1,2). This latter function involves NM23-H4-mediated intermembrane transfer of cardiolipin (CL) from the mitochondrial inner membrane to the mitochondrial surface. Interestingly, both functions seem to involve an interaction of NM23-H4 with OPA1, a dynamin-like GTPase of the mitochondrial inner membrane. First, NM23-H4 directly fuels OPA1 with GTP via its NDPK bioenergetic function (3). In addition, also the CL transfer activity of NM23-H4 seems to depend on OPA1, since knock-down of OPA1 in HeLa cells reduces CL transfer in NM23-H4 WT expressing cells as compared to those expressing CL-transfer incompetent NM23-H4 mutants. Thus, OPA1 seems to be a negative regulator of the CL transfer function of NM23-H4. Our current model suggests that NM23-H4/OPA1 complexes exist in healthy mitochondria at the inner membrane to maintain OPA1 functions in membrane fusion and dynamics. Upon OPA1 cleavage, an early step during mitophagy, NM23-H4 may be released from these complexes, allowing simultaneous interaction of the hexameric NM23-H4 complex with inner and outer mitochondrial membrane and CL transfer.(1) Schlattner et al. (2015) Naunyn Schmiedebergs Arch. Pharmacol. 388, 271-8.(2) Kagan et al. (2016) Cell Death Diff. 23, 1140-51.(3) Boissan et al. (2014) Science 344, 1510-5.