The well-established function of the mitochondrial intermembrane space protein NME4 (also called NDPK-D or NM23-H4) 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. This latter function involves NME4-mediated intermembrane phospholipid transfer activity, leading to externalization of cardiolipin (CL) from the mitochondrial inner membrane to the mitochondrial surface. Interestingly, both functions seem to involve an interaction of NME4 with OPA1, a dynamin-like GTPase of the mitochondrial inner membrane. First, NME4 directly fuels OPA1 with GTP via its NDPK bioenergetic activity. However, also the CL transfer activity of NME4 is related to OPA1, since OPA1 seems to be a negative regulator of this NME4 CL transfer. Our current model suggests that NME4/OPA1 complexes exist in healthy mitochondria to maintain OPA1 functions in inner membrane fusion and dynamics. Upon OPA1 cleavage, an early step during mitophagy, NME4 may be released from these complexes, allowing simultaneous interaction of the hexameric NME4 complex with inner and outer mitochondrial membrane and CL transfer. Our most recent data on HeLa cells reveal that ablating either NME4 function, phosphotransfer or lipid transfer, affects cell morphology and motility