Mitochondrial shuttle

The mitochondrial shuttles are systems used to transport reducing agents across the inner mitochondrial membrane. NADH as well as NAD+ cannot cross the membrane, but it can reduce another molecule like FAD and [QH₂] that can cross the membrane, so that its electrons can reach the electron transport chain.

The two main systems in humans are:

Name	In To mitochondrion	To ETC	Out To cytosol
Glycerol phosphate shuttle	Glycerol 3-phosphate	QH2 (~1.5 ATP)	Dihydroxyacetone phosphate
Malate-aspartate shuttle	Malate	NADH (~3 ATP)	Oxaloacetate[1]/aspartate

In humans, the glycerol phosphate shuttle is primarily found in brown adipose tissue, as the conversion is less efficient, thus generating heat, which is one of the main purposes of brown fat. It is primarily found in babies, though it is present in small amounts in adults around the kidneys and on the back of our necks.[1] The malate-aspartate shuttle is found in much of the rest of the body.

The mitochondrial shuttle contains a system of mechanisms used to transport metabolites that lack a protein transporter in the membrane, such as oxaloacetate. The malate shuttle is an example of a mitochondrial shuttle which allows the mitochondria to move electrons from NADH without the consumption of metabolites. The malate shuttle uses two antiporters to transport metabolites and keep balance within the mitochondrial matrix and cytoplasm. On the cytoplasmic side a transaminase enzyme is used to remove an amino group from aspartate which is converted into oxaloacetate, then malate dehydrogenase enzyme uses an NADH cofactor to reduce oxaloacetate to malate which can be transported across the membrane because of the presence of a transporter. Once the malate is inside the matrix its converted back to oxaloacetate, which is converted to aspartate and can be transported back outside the mitochondria to allow the cycle to continue. The movement of oxaloacetate across the membrane transports electrons and is known as the outer ring. The inner ring primary function is not to move electrons but regenerate the metabolites. The transamination of oxaloacetate to aspartate is achieved through the use of glutamate. Glutamate is transported with aspartate via antiporter, thus as one aspartate leaves the cell, a glutamate enters. Glutamate in the matrix is converted into an a-ketoglutarate which is transported in an antiporter with malate. In the cytoplasmic side a-ketoglutarate is converted back into glutamate when aspartate is converted back to oxaloacetate. To summarize, the malate/a-ketoglutarate antiporter functions move electrons while the aspartate/glutamate antiporter moves amino groups. This allows the mitochondria to receive the substrates it needs for functionality in an efficient manner.[2]

Most cancer cells cause mutation in the bodies metabolic activities to increase glucose metabolism in order to rapidly proliferate. Mutations that increase the cells metabolic activity and turn a normal cell into a tumor cell are called oncogenes. Cancer cells are unlike many other cells. They have very little vulnerabilities, but experiments in which the inhibition of transamination of malate-shuttle slowed proliferation due to the fact metabolism of glucose was being slowed.[3]

See also

• Mitochondrial carrier

Notes and references

1. Silva, Pedro. "then chemical logic behind ... Fermentation and Respiration" Archived 2008-09-17 at the Wayback Machine, Universidade Fernando Pessoa, 2002-01-04. Retrieved on 2009-04-02.
2. Garrett, Reginald H. (11 February 2016). Biochemistry. Grisham, Charles M. (Sixth ed.). Boston, MA. ISBN 978-1-305-57720-6. OCLC 914290655.
3. Ilic, Nina; Birsoy, Kıvanç; Aguirre, Andrew J.; Kory, Nora; Pacold, Michael E.; Singh, Shambhavi; Moody, Susan E.; DeAngelo, Joseph D.; Spardy, Nicole A.; Freinkman, Elizaveta; Weir, Barbara A. (25 April 2017). "PIK3CA mutant tumors depend on oxoglutarate dehydrogenase". Proceedings of the National Academy of Sciences of the United States of America. 114 (17): E3434–E3443. doi:10.1073/pnas.1617922114. ISSN 1091-6490. PMC 5410781. PMID 28396387.