Multiple metabolic pathways fuel the truncated tricarboxylic acid cycle of the prostate to sustain constant citrate production and secretion.

The prostate is metabolically unique: it produces high levels of citrate for secretion via a truncated tricarboxylic acid (TCA) cycle to maintain male fertility. In prostate cancer (PCa), this phenotype is reprogrammed, making it an interesting therapeutic target. However, how the truncated prostate TCA cycle works is still not completely understood.

We optimized targeted metabolomics in mouse and human organoid models in ex vivo primary culture. We then used stable isotope tracer analyses to identify the pathways that fuel citrate synthesis.

First, mouse and human organoids were shown to recapitulate the unique citrate-secretory program of the prostate, thus representing a novel model that reproduces this unusual metabolic profile. Using stable isotope tracer analysis, several key nutrients were shown to allow the completion of the prostate TCA cycle, revealing a much more complex metabolic profile than originally anticipated. Indeed, along with the known pathway of aspartate replenishing oxaloacetate, glutamine was shown to fuel citrate synthesis through both glutaminolysis and reductive carboxylation in a GLS1-dependent manner. In human organoids, aspartate entered the TCA cycle at the malate entry point, upstream of oxaloacetate. Our results demonstrate that the citrate-secretory phenotype of prostate organoids is supported by the known aspartate-oxaloacetate-citrate pathway, but also by at least three additional pathways: glutaminolysis, reductive carboxylation, and aspartate-malate conversion.

Our results add a significant new dimension to the prostate citrate-secretory phenotype, with at least four distinct pathways being involved in citrate synthesis. Better understanding this distinctive citrate metabolic program will have applications in both male fertility as well as in the development of novel targeted anti-metabolic therapies for PCa.

Molecular metabolism. 2022 May 19 [Epub ahead of print]

Lilianne Frégeau-Proulx, Aurélie Lacouture, Line Berthiaume, Cindy Weidmann, Mario Harvey, Kevin Gonthier, Jean-François Pelletier, Bertrand Neveu, Cynthia Jobin, Dominic Bastien, Alain Bergeron, Yves Fradet, Louis Lacombe, Isabelle Laverdière, Chantal Atallah, Frédéric Pouliot, Étienne Audet-Walsh

Endocrinology - Nephrology Research Axis, CHU de Québec - Université Laval Research Center, Québec, QC, Canada; Department of molecular medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada; Centre de recherche sur le cancer de l'Université Laval, Québec, QC, Canada., Endocrinology - Nephrology Research Axis, CHU de Québec - Université Laval Research Center, Québec, QC, Canada; Centre de recherche sur le cancer de l'Université Laval, Québec, QC, Canada., Centre de recherche sur le cancer de l'Université Laval, Québec, QC, Canada; Oncology Axis, Centre de recherche du CHU de Québec - Université Laval, Québec, QC, Canada., Centre de recherche sur le cancer de l'Université Laval, Québec, QC, Canada; Oncology Axis, Centre de recherche du CHU de Québec - Université Laval, Québec, QC, Canada; Department of surgery, Faculty of Medicine, Université Laval, Québec, QC, Canada., Centre de recherche sur le cancer de l'Université Laval, Québec, QC, Canada; Oncology Axis, Centre de recherche du CHU de Québec - Université Laval, Québec, QC, Canada; Faculty of Pharmacy, Université Laval, Québec, QC, Canada; Department of pharmacy, CHU de Québec - Université Laval, Québec, QC, Canada., Department of pathology, CHU de Québec - Université Laval, Québec, QC, Canada., Endocrinology - Nephrology Research Axis, CHU de Québec - Université Laval Research Center, Québec, QC, Canada; Department of molecular medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada; Centre de recherche sur le cancer de l'Université Laval, Québec, QC, Canada. Electronic address: .

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