![]() Whether disrupting mitochondrial fission would have a therapeutic effect in pancreatic cancer was unknown. Pancreatic cancer is frequently driven by oncogenic KRAS, the downstream signaling of which activates DRP1 and promotes mitochondrial fission ( 10). Genetic or pharmacological inhibition of mitochondrial fission promotes mitochondrial fusion and suppresses OXPHOS. These proof-of-principle experiments demonstrate the critical nature of mitochondrial dynamics and how they could potentially be exploited therapeutically against PDAC. We provide evidence that mitochondrial fusion induces mitophagy in pancreatic cancer cells, which may selectively reduce the functional mitochondrial mass in tumors. Moreover, we found that the induction of mitochondrial fusion correlates with less mitochondrial mass and reduced OXPHOS compared with controls. Indeed, we found that the genetic or pharmacologic activation of mitochondrial fusion reduces PDAC growth and improves survival in mouse models of pancreatic cancer. We also reasoned that such an approach may have a favorable therapeutic ratio, since mitochondrial fusion is more frequently observed in normal cells ( 9). We hypothesized that shifting the balance of mitochondrial dynamics toward mitochondrial fusion in PDAC cells would normalize their function and reduce oncogenicity, as has been suggested in previous cell culture studies ( 8). Pancreatic cancer cells exhibit highly fragmented mitochondria ( 7), which suggests basal mitochondrial dynamics that favor mitochondrial fission. On the other hand, the GTPase dynamin-related protein-1 (DNM1L/DRP1) regulates mitochondrial fission, and its dysfunction may promote unregulated mitochondrial fusion ( 6). Dysfunction or deficits in MFN expression can lead to unopposed mitochondrial fission and possibly disease, such as Charcot-Marie-Tooth type 2A syndrome, which is caused by an autosomal dominant mutation in MFN2 ( 5). The mitofusin family of proteins (MFN1 and MFN2) positively regulate the fusion of mitochondria by bringing together the outer mitochondrial membranes. The morphology of these networked mitochondria is regulated by a few key proteins. The homeostatic processes of fission and fusion in response to cellular demands is often referred to as mitochondrial dynamics. In other cases, mitochondria fragment into smaller organelles through a controlled process called mitochondrial fission, which is often a response to oxidative stress ( 4). For instance, mitochondria join together in a process called mitochondrial fusion, which is critical for organelle quality control ( 3). Mitochondria within a cell can collectively alter their structures to optimize their metabolic functions in response to cellular insults ( 2). Pancreatic ductal adenocarcinoma (PDAC) relies on energy produced by oxidative phosphorylation (OXPHOS) from the mitochondria to grow and metastasize ( 1). These data suggest that mitochondrial fusion is a specific and druggable regulator of pancreatic cancer growth that could be rapidly translated to the clinic. We found that the chief tumor-suppressive mechanism of mitochondrial fusion was enhanced mitophagy, which proportionally reduced mitochondrial mass and ATP production. Notably, we found that oral leflunomide, an FDA-approved arthritis drug, promoted a 2-fold increase in Mfn2 expression in tumors and was repurposed as a chemotherapeutic agent, improving the median survival of mice with spontaneous tumors by 50% compared with vehicle. Mitochondrial fusion was achieved by genetic or pharmacologic inhibition of dynamin-related protein-1 (Drp1) or through overexpression of mitofusin-2 (Mfn2). Here, we present evidence that normalizing the fragmented mitochondria of pancreatic cancer via the process of mitochondrial fusion reduces OXPHOS, which correlates with suppressed tumor growth and improved survival in preclinical models. PDAC cells exhibit abnormally fragmented mitochondria that are essential to the oncogenicity of PDAC, but it was unclear if this mitochondrial feature was a valid therapeutic target. Pancreatic ductal adenocarcinoma (PDAC) requires mitochondrial oxidative phosphorylation (OXPHOS) to fuel its growth however, broadly inhibiting this pathway might also disrupt essential mitochondrial functions in normal tissues.
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