A Mutation in Mouse MT-ATP6 Gene Induces Respiration Defects and Opposed Effects on the Cell Tumorigenic Phenotype

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Abstract
As the last step of the OXPHOS system, mitochondrial ATP synthase (or complex V) is responsible for ATP production by using the generated proton gradient, but also has an impact on other important functions linked to this system. Mutations either in complex V structural subunits, especially in mtDNA-encoded ATP6 gene, or in its assembly factors, are the molecular cause of a wide variety of human diseases, most of them classified as neurodegenerative disorders. The role of ATP synthase alterations in cancer development or metastasis has also been postulated. In this work, we reported the generation and characterization of the first mt-Atp6 pathological mutation in mouse cells, an m.8414A>G transition that promotes an amino acid change from Asn to Ser at a highly conserved residue of the protein (p.N163S), located near the path followed by protons from the intermembrane space to the mitochondrial matrix. The phenotypic consequences of the p.N163S change reproduce the effects of MT-ATP6 mutations in human diseases, such as dependence on glycolysis, defective OXPHOS activity, ATP synthesis impairment, increased ROS generation or mitochondrial membrane potential alteration. These observations demonstrate that this mutant cell line could be of great interest for the generation of mouse models with the aim of studying human diseases caused by alterations in ATP synthase. On the other hand, mutant cells showed lower migration capacity, higher expression of MHC-I and slightly lower levels of HIF-1α, indicating a possible reduction of their tumorigenic potential. These results could suggest a protective role of ATP synthase inhibition against tumor transformation that could open the door to new therapeutic strategies in those cancer types relying on OXPHOS metabolism.
Funding Information
  • Ministerio de Ciencia e Innovación (PGC2018-095795-B-I00, Grupo de Referencia E35_17R, LMP220_21, ICoMICS No 101018587, PRDAR21487SOLE)
  • Gobierno de Aragón (PGC2018-095795-B-I00, Grupo de Referencia E35_17R, LMP220_21, ICoMICS No 101018587, PRDAR21487SOLE)
  • European Research Council (ERC) (PGC2018-095795-B-I00, Grupo de Referencia E35_17R, LMP220_21, ICoMICS No 101018587, PRDAR21487SOLE)
  • Spanish Association Against Cancer in Aragón (PGC2018-095795-B-I00, Grupo de Referencia E35_17R, LMP220_21, ICoMICS No 101018587, PRDAR21487SOLE)

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