Recent study proposed that the citrate–malate shuttle may contribute to sustaining cancer cells through a β-oxidation-citrate–malate shuttle metabolic pathway. In normal cells, β-oxidation produces acetyl-CoA which enters the Krebs cycle to produce ATP, and β-oxidation cannot continue if the Krebs cycle is impaired and acetyl-CoA accumulates. However, cancer cells may carry out continuous β-oxidation by connecting it to the citrate–malate shuttle. The new metabolic pathway consists of mitochondrial transport proteins and several enzymes, including ATP-citrate lyase (ACLY) and malate dehydrogenases 1 and 2 (MDH1 and MDH2). The proposed metabolic pathway may explain the Warburg effect – that cancer cells produce energy through a suboptimal pathway – and hypoxia in cancer.
The energy efficiency of this pathway is 3.76 times less than the normal β-oxidation Krebs cycle pathway, only producing 26 moles instead of 98 moles of ATP from 1 mole of palmitate.
It is still unsure whether this pathway exists in cancer cells. Factors preventing this pathway from occurring includes lipotoxicity of palmitate and stearate.