ATP-Synthasis

ATP- Synthesis

1. Introduction

The nucleotide Adenosine- triphosphate (ATP) has a main role in the energy pathway. ATP synthesis is a basic requirement in living cells. ATP can be produced by substrate-level phosphorylation (6.1. table) or by the most high- energy process, called oxidative phosphorylation. It consists of four different complexes (6.2. table). The required electrons are obtained by the delivery from electrons via electron- carriers (NADH, FADH2). The energy of the electron transfer is stored in the proton- gradient. The resulting proton motive edges the ATP- synthesis and the reduction of O2 to H2O. The final stages of the process is catalysed by the complex F1F0- ATP synthase (6.3. graphic)

2. Medical aspects

Defects of ATP synthase, disorders of ATP synthesis and ATP depletion are important in genetic research. It is recognized as a frequent cause of human disease.1 The current inadequacy of treatment in patients with mitochondrial disorders highlights the need to develop strategies to heal it.

3. Reduced ATP synthesis – disorders

Defects in the enzyme ATP synthase – as a key component in mitochondrial energy conversation - cause mitochondrial diseases. Deficiency can be described, as primary (mutations) or secondary (increased production of free oxygen radicals, decreased intermediary metabolism, metabolic acidosis). The subunits of F0F1- ATPase are encoded by the nuclear and mitochondrial genome. Disorders can have their origin here, or in the levels of transcription, translation and folding of the enzyme. Two mitochondrially encoded subunits of F0F1- ATPase (∝, A6L) mutations and one nuclear mutation (ATP12) has been identified.2 Clinical manifestation is neuropathy, ataxie and rethinis prigmentosa  (NRAP syndrome) etc. Several point mutations in the ATP6 gene can be distinguished. For example a mutation at position nt8993 results in a replacement of leucine by arginine and leads to heteroplasmy and NRAP syndrome. ATP6 mutations can cause disturbance of the intraenzyme coupling of protons.3 A secondary deficiency is reactive oxygen species. They lead to an unproductive electron transfer between complex I and III (table 2) and decrease the respiratory chain. This includes processes, which lead to a reduced content of ATP.4 Those patients show an uniform phenotype with hypertrophic cardiomyopathy, and elevated levels of acid in urine. Aging of post- mitotic tissue is associated with a continuous decrease of mitochondrial capacity to produce ATP. This, and enhanced oxidative stress triggers senescent disfunction of lived post – mitotic cells, as e.g. neurons and cardiac myocytes.5

4. Therapeutic ATP synthase deficiencies.

Therapeutic approach is limited. It encounters difficulties because of multiple mtDNA copies per cell, heteroplasmy and complexity of manipulating the mitochondrial genome in living cells. One treatment is the allotropic expression of mtDNA- encoded polypeptides. A protein is therefore synthesized in the cytosol from an alternative nuclear vision and fused to a mitochondrial targeting sequence (MTS). Replication of mutant mtDNA (heteroplasmy) can be inhibited trough a sequence- specific binding of peptid nucleic acids (PNAs) using a zinc finger metylase. This allows a sequence- specific modification of mtDNA.6 Low- level laser therapy (LLLT) or photobiomodulation can be used in physical medicine to increase the ATP amount, if the reduced ATP is not caused by mutations. Low- power laser light (λ = 632- 1064nm) induces a photochemical reaction in complex IV of oxidative phosphorylation chain.7

5. Conclusion

Efficient therapy is missing. Genetic research has a big impact on medical treatment.

6. Annex

'''6.1. Table. ATP synthesis – other reactions8'''

'''6.2. Table. Complexes of oxidative phosphorylation9'''

6.3. Graphic ATP- Synthase10

https://classconnection.s3.amazonaws.com/713/flashcards/971713/jpg/atp_synthase-145F4DA86DD36E066F9.jpg

7. References

1 S. Dimauro, Mitochondrial medicine, Biochim. Biophy. Acta 1659 (2004) 107 - 114.

2 http://www.sciencedirect.com/science/article/pii/S0167488908002395 on 26/11/2015.

3 I.J. Holt, A.E. Harding, R.K.H. Petty, J.A. Morgan-Hughes, A new mito- chondrial disease associated with mitochondrial DNA heteroplasmy, Am. J. Hum. Genet. 46 (1990) 428–433.

4 http://sciencedirect.com/article/pli/S000527806001022 on 29/11/2015.

5 http://iovs.arvojournals.org/pdfaccess.ash?url=data/Journals/IOVS/933252 on 30/11/2015.

6 http://sciencedirect.com/article/pli/S000527806001022 on 29/11/2015.

7 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065857 on 30/11/2015.

8 Nelson, Cox, Lehninger Biochemie, Springer Berlin- Heidelberg, 4th edition, Heidelberg 2011, p. 968.

9 Nelson, Cox, Lehninger Biochemie, Springer Berlin- Heidelberg, 4th edition, Heidelberg 2011, p. 944-64.

10 https://classconnection.s3.amazonaws.com/713/flashcards/971713/jpg/atp_synthase-145F4DA86DD36E066F9_jpg, (30/11/2015).