Citrate–malate shuttle
As the inner mitochondrial membrane is impermeable to acetyl-CoA, the shuttle system is essential to fatty acid synthesis in the cytosol.
[3] The name of the citrate-malate shuttle is derived from the two intermediates – short-lived chemicals that are generated in a reaction step and consumed entirely in the next – citrate and malate that carry the acetyl-CoA molecule across the mitochondrial double membrane.
The citrate–malate shuttle is present in humans and other higher eukaryotic organisms and is closely related to the Krebs cycle.
Mitochondria is a double-membrane structure in the body cell that generates and transports essential metabolic products.
A cycle is formed by the system, ensuring that the conversion between acetylene, oxaloacetate, citrate, and malate can continue without the need for foreign molecule addition.
The citrate-malate shuttle allows the cell to produce fatty acid with excess acetyl-CoA for storage.
Acetyl-CoA is generated in the mitochondrial matrix from two sources: pyruvate decarboxylation in glycolysis and the breakdown of fatty acids through β-oxidation, which are both essential pathways of energy production in humans.
[9] Otherwise, fatty acid β-oxidation occurs, and acetyl-CoA is required to generate ATP through the Krebs cycle.
Fatty acid synthesis is hence hindered, and the body would not be able to store excess energy as efficiently as a normal subject.
[9] Usually, oxaloacetate in the Krebs cycle is generated from the carboxylation of pyruvate in the mitochondrion; however, malate generated in the cytosol can also enter the mitochondrion through the transport protein located in the inner mitochondrial membrane to directly join the Krebs cycle.
It releases acetyl-CoA and provides NADPH for fatty acid synthesis, and, in subsequent pathways, generates NAD+ for glycolysis.
Citrate also activates acetyl-CoA carboxylase, an enzyme that is essential in the fatty acid synthesis pathway.
[11] Citrate-malate shuttle might partly or completely replace the function of the Krebs cycle in cancer cell metabolism.
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).
However, apoptosis is disrupted in cancer cells, allowing them to divide and grow uncontrollably, potentially invading other tissues or organs.
[16] Hepatocellular carcinoma (HCC) is a prevalent type of liver cancer that accounts for over 80% of cases.
[17] It is lethal cancer due to the remarkable drug tolerance, spread potential and high chance of relapse.
Scientists have carried out many kinds of research in finding out the risk factors of HCC progression.
In high obesity or insulin resistance (diabetes) patients, their body contains large amounts of fatty acid,[15] the shuttle system might not generate sufficient NAD+ to metabolize the fat efficiently.
[17] A high frequency mutated gene in a wide range of cancers, Ras oncogene, has a significantly close association to HCC.
The research of Dalian Medical University[17] shows that there is a noticeable increase in the HCC patients’ citrate and malate levels, suggesting the possibility of higher activity of citrate–malate shuttle.
In liver cancer cells, the TCA cycle is blocked, causing accumulation of excess pyruvate.
This leads to significant decrease in the energy production of our body cells, causing severe metabolic diseases.
It indicates that this gene is favourable for the survival of a species in response to the environmental features, so it is preserved and passed along the generation.
