jane-buchanan@uiowa.edu
Mentor: Eric Taylor, Ph.D.
Lab Room: 3212 PBDB
Lab Phone: 319-335-7500

Disruption of the mitochondrial pyruvate carrier drives non-essential amino acid synthesis and growth in cancer cells

In order to sustain rapid proliferation, cancer cells undergo metabolic reprogramming to increase protein, nucleotide, and lipid synthesis. A classic example of this is the Warburg effect, a phenomenon in which certain cancer types upregulate glycolysis at the expense of oxidative phosphorylation in order to channel glycolytic intermediates into biosynthetic substrates. We predict that the deletion or downregulation of the mitochondrial pyruvate carrier (MPC) is also a type of metabolic reprogramming used to drive cancer cell proliferation. The MPC facilitates the transport of pyruvate from the cytoplasm into the mitochondria, linking glycolysis and the TCA cycle. Downregulation of the MPC is correlated with metastasis and poor survival in certain cancer types. Studies have also shown that MPC disruption increases cell proliferation. Research groups have proposed that MPC disruption increases cellular proliferation by promoting the Warburg effect or by altering stem cell fate. However, our preliminary studies suggest that MPC inhibition drives ammonia into the mitochondria in the form of alanine, which the cell then recycles into non-essential amino acids that are critical for protein synthesis and growth.

Soranno DE, Gil HW, Kirkbride-Romeo L, Altmann C, Montford JR, Yang H, Levine A, Buchanan J, Faubel S. Matching Human Unilateral AKI, a Reverse Translational Approach to Investigate Kidney Recovery after Ischemia. J Am Soc Nephrol. 2019 May 9. pii: ASN.2018080808. doi: 10.1681/ASN.2018080808. [Epub ahead of print] PubMed PMID: 31072827.

Tompkins S, Sheldon R, Raukhorst A, Noterman M, Solst S, Buchanan J, Mapuskar K, Gray L, Oonthanpan L, Sharma A, Scerbo D, Dupuy A, Spitz D, Taylor E. Disrupting mitochondrial pyruvate uptake directs glutamine into the TCA cycle away from glutathione synthesis and impairs hepatocellular tumogenesis. Cell Reports. 2019 September. 28, 2608-2619. PMID: 31484072.