The Methionine-Mitochondria Axis in Cancer: Metabolic Cross-Talk and Therapeutic Vulnerabilities

Abstract Purpose of Review This article describes the recent discoveries on how the amino acid methionine alters mitochondrial metabolism to support tumor function and growth. A detailed understanding of these mechanisms of cross-talk between the methionine cycle and mitochondria will empower the discovery and development of new metabolism-targeting cancer therapies. Recent Findings Methionine and metabolites of the methionine cycle are increasingly appreciated to have both direct and indirect roles in regulating mitochondrial metabolism, which are critical for survival, growth, and treatment-resistance in tumors. Recent work has discovered multiple mitochondrial transporters that directly connect tumor use of methionine-derived S-adenosylmethionine (SAM) to mitochondrial function. Carnitine is synthesized from SAM-mediated methylation of lysine and is critical for tumor energy generation by fatty acid oxidation. Tumors depend on mitochondrial transport of SAM to support methylation reactions and oxidative phosphorylation. Purine synthesis is supported by mitochondrial one-carbon units from the folate cycle in tumors, which requires remethylation of homocysteine to form methionine to prevent folate trapping. Preclinical and clinical studies investigating both pharmacological and nutritional interventions are uncovering the mechanisms by which mitochondrial function depends on methionine metabolism. Further exploration in this area will define both the targets and specific interventions with the greatest promise for the treatment of cancer patients. Summary Methionine metabolism influences many aspects of mitochondrial function, including energy generation, antioxidant defenses, and lipid composition. Understanding how tumors co-opt these processes and their dependence on the amino acid nutrient methionine provides an opportunity for new cancer therapies.