Dissecting the physical and functional interaction between RCC1L and NME4

The GTPase protein OPA1, which regulates inner mitochondrial membrane (IMM) fusion and cristae structure, is one of the most important players in mitochondrial dynamics. I speculate that its two interactors, the nucleotide diphosphate kinase NME4 and the guanine nucleotide exchange factor RCC1L, elevate OPA1 activity in pancreatic ductal adenocarcinoma (PDAC) cells, respectively by generating GTP and loading it onto OPA1. Interestingly, we previously found that RCC1L and NME4 are over-represented in the mitochondrial proteome of PDAC cells compared to non-transformed pancreatic epithelial cells, and that high NME4 expression is associated to poor prognosis in human patients. This suggests that these two proteins play a role in PDAC progression, possibly through regulation of OPA1 function. Indeed, downregulation of either NME4 or RCC1L impairs mitochondrial network, ultrastructure, and mitochondrial respiration in PDAC cells lines, while OPA1 overexpression promotes pancreatic carcinogenesis in autochthonous mouse models. My thesis aims to dissect the physical interaction between RCC1L and NME4 and understand whether OPA1 activity depends on this protein nexus. My work unveils molecular mechanisms the contribute to the malignant evolution of PDAC, which is possibly the deadliest form of cancer with dismal survival and limited therapeutic options.