Abstract
Mitochondria are dynamic organelles that constantly alter their shape through the recruitment of specialized proteins, like mitofusin-2 (Mfn2) and dynamin-related protein 1 (Drp1). Mfn2 induces the fusion of nearby mitochondria, while Drp1 mediates mitochondrial fission. We previously found that the genetic or pharmacological activation of mitochondrial fusion was tumor suppressive against pancreatic ductal adenocarcinoma (PDAC) in several model systems. The mechanisms of how these different inducers of mitochondrial fusion reduce pancreatic cancer growth are still unknown. Here, we characterized and compared the metabolic reprogramming of these three independent methods of inducing mitochondrial fusion in KPC cells: overexpression of Mfn2, genetic editing of Drp1, or treatment with leflunomide. We identified significantly altered metabolites via robust, orthogonal statistical analyses and found that mitochondrial fusion consistently produces alterations in the metabolism of amino acids. Our unbiased methodology revealed that metabolic perturbations were similar across all these methods of inducing mitochondrial fusion, proposing a common pathway for metabolic targeting with other drugs.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) relies on mitochondrial respiration through remodeling of the electron transport chain in order to sustain its proliferative abilities [1,2]
Fragmented mitochondrial morphology decreased from 68.2% to 14.8% after treatment with leflunomide when compared to the vehicle control (Figure 2C, p < 0.0001)
Using our overlapped discriminant metabolite list for sub-pathway analysis, we discovered that even our more limited metabolite set was able to recapitulate these trends in metabolic reprogramming in each independent method of mitochondrial fusion induction
Summary
Pancreatic ductal adenocarcinoma (PDAC) relies on mitochondrial respiration through remodeling of the electron transport chain in order to sustain its proliferative abilities [1,2]. Mitochondria undergo fusion and fission in response to external stimuli to optimize metabolic functions and to promote turnover of damaged organelles through mitophagy [5]. This balance between mitochondrial fusion and fission is regulated by two key molecules: mitofusin-2 (Mfn2) and dynamin-related protein 1 (Drp). Leflunomide, an FDA-approved drug for rheumatoid arthritis, was identified as a pharmacologic activator of mitochondrial fusion through upregulation of Mfn2 [8] Capitalizing on this mode of action, we treated pancreatic cancer cells with leflunomide, which phenocopied the tumor suppressive effects of Drp inhibition [3]. The metabolic mechanisms by which mitochondrial fusion reduce PDAC growth are unknown
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