Respiratory Supercomplexes Promote Mitochondrial Efficiency and Growth in Severely Hypoxic Pancreatic Cancer

Abstract

SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive fibrosis and hypovascularization, resulting in significant intratumoral hypoxia (low oxygen) that contributes to its aggressiveness, therapeutic resistance, and high mortality. Despite oxygen being a fundamental requirement for many cellular and metabolic processes, and the severity of hypoxia in PDAC, the impact of oxygen deprivation on PDAC biology is poorly understood. Investigating how PDAC cells survive in the near absence of oxygen, we find that PDAC cell lines grow robustly in oxygen tensions down to 0.1%, maintaining mitochondrial morphology, membrane potential, and the oxidative metabolic activity required for the synthesis of key metabolites for proliferation. Disrupting electron transfer efficiency by targeting mitochondrial respiratory supercomplex assembly specifically affects hypoxic PDAC proliferation, metabolism, and in vivo tumor growth. Collectively, our results identify a mechanism that enables PDAC cells to thrive in severe, oxygen-limited microenvironments.

Targeting Fibrosis: The Bridge That Connects Pancreatitis and Pancreatic Cancer

“…In addition, pancreatic fibrosis leads to hypoxia in the pancreatic tumor, which causes more oxidative stress response, promoting tumor aggressiveness, increasing drug resistance in cancer cells, and thereby causing higher patient mortality rates [ 155 ]. Interestingly, NUPR1, a stress protein activated in pancreatitis, promotes fibrosis, inflammation, and cancer initiation and development, indicating that NUPR1 is essential for TME.…”

Transporters at the Interface between Cytosolic and Mitochondrial Amino Acid Metabolism

“…Although glutaminolysis provides cells with the majority of carbon necessary to synthesize aspartate, in cancer subtypes driven by TCA cycle deficiencies (e.g., SDH-or FH-deficiency), pyruvate carboxylase activity can divert glucose-derived pyruvate to supply oxaloacetate necessary for this anabolic function [79][80][81][82][83][84]. This shift to PC-dependent aspartate synthesis was also observed in PDAC tumors in vivo and in breast and lung cancer cell lines exposed to hypoxic oxygen tensions [77,85]. Taken together, aspartate is a critical anabolic metabolite necessary to supply nucleotides for proliferating cancer cells; however, its synthesis from glutamineand/or glucose-derived pathways are complex and highly dependent on the environmental context and nutrient availability.…”

“…Hypoxia reportedly suppresses mitochondrial aspartate biosynthesis via HIF1α-dependent down-regulation of GOT1 and GOT2 in Von Hippel-Lindau (VHL)-deficient renal carcinoma cells [ 76 ]. However, pancreatic cancer cells have been shown to sustain aspartate biosynthetic fluxes in oxygen tensions as low as 0.1% O 2 through activity of Complex III+IV containing respiratory supercomplexes, which are suggested to promote efficient respiration in limiting oxygen environments [ 77 ]. Notably, maximal HIF stabilization occurs in ~1% O 2 , well above tensions where oxygen becomes limiting for mitochondrial respiration [ 78 ].…”

“…Although glutaminolysis represents a major carbon source for TCA cycle intermediates in normal conditions, hypoxia and/or mitochondrial dysfunction leads to significant rewiring of glutamine metabolism through reductive carboxylation pathways to support lipogenic flux [ 214 , 215 , 216 , 217 , 218 ]. However, many pancreatic cancer cell lines are capable of sustaining oxidative TCA cycling even at 0.1% O 2 , and Yoo et al demonstrate that SLC1A5_var activity in pancreatic cancer cells is important for ATP generation from glutamine in hypoxia [ 77 , 208 ]. SLC1A5_var activity promoted glutathione production and ROS scavenging in response to oxygen limitation and was important for gemcitabine resistance mechanisms in cancer cells.…”

Metabolic Reprogramming of Cancer Cells during Tumor Progression and Metastasis

“…Of note, the ETC can function at near-anoxic levels [ 71 ] and, in fact, its activity was only reported to be limited in intracellular oxygen levels of 0.3% or below [ 72 ]. Indeed, pancreatic ductal adenocarcinoma (PDAC) cells require ETC activity to proliferate in severe hypoxia, with a 0.1% oxygen level [ 73 ].…”