The role of RCC1L and NME4 in mitochondrial cristae remodeling and pancreatic cancer progression

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, primarily due to late diagnosis and lack of efficient therapies. PDAC carcinogenesis occurs through multi-step progression, in that tumor onset is preceded by the formation of increasingly dysplastic lesions that can evolve into frank carcinoma. This is due to the accumulation of genetic mutations but also to step-wise metabolic reprogramming, which includes changes in mitochondrial structure and function. This thesis aims to understand the role of two highly-interconnected proteins upregulated in the aggressive stages of PDAC and linked to nucleotide homeostasis and mitochondrial cristae organization. I found that the nucleotide diphosphate kinase NME4 and the guanine nucleotide exchange factor RCC1L cooperate to increase the activity of Optic Atrophy Protein 1 (OPA1). Silencing of either NME4 or RCC1L widens intramitochondrial cristae and dampens the cellular respiratory capacity. However, it also significantly impacts whole-cell metabolism and ultimately inhibits cell proliferation. In this thesis, I will show how these proteins are functionally linked to promote PDAC carcinogenesis.