Quintana-Cabrera 2015 Abstract MiPschool London 2015

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Cristae remodeling by Opa1 modulates mitochondrial bioenergetics by promoting ATPase dimerization and activity.

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Quintana-Cabrera R, Corrado M, Scorrano L (2015)

Event: MiPschool London 2015

Mitochondrial cristae function as a membrane anchor for respiratory complexes and are required for normal mitochondrial respiration [1]. Opa1, a mitochondrial pro-fusion protein, contributes to maintain the cristae structure thus favoring the formation of respiratory supercomplexes and OXPHOS efficiency [2]. However, whether Opa1 influences key bioenergetic parameters of mitochondria remains still unclear.

Here, we report that Opa1 modulates mitochondrial bioenergetics by impinging on ATPase. Upon complex III inhibition, subsequent matrix acidification and loss of membrane potential are prevented in Opa1tg mouse adult fibroblasts (MAFs), corresponding to a higher efficiency of the reversal activity of mitochondrial ATPase. Using genetic and pharmacological approaches we found that cristae stabilization by Opa1 promotes ATPase dimerization, which accounts for the higher activity of the enzyme in Opa1tg MAFs. Conversely, dimer disruption by downregulation of the subunit e of the ATPase reverted Opa1 effects in mitochondrial bioenergetics. In agreement with a role of cristae shape in determining ATPase dimerization, inner membrane remodeling by Bid [3] disrupted dimers and promoted matrix acidification, which was partially prevented in Opa1tg cells. The ability of Opa1tg to sustain mitochondrial function upon CIII inhbition also prevented the generation of ROS in an ATPase dependent manner; accordingly, we observed lower cell death of Opa1tg MAFs under forced ATP production by mitochondria, where ROS production is increased.

In sum, the regulation of ATPase activity by Opa1 accounts for its pro-survival effects and indicates that Opa1 is a key regulator of mitochondrial bioenergetics and redox status.


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Organism: Mouse  Tissue;cell: Fibroblast 





Affiliations

1-Dulbecco-Telethon Inst, Venetian Inst Mol Med Padova, Italy. - ruben310@usal.es

2-Dept Biol, Univ Padova

References

  1. Frey TG, Mannella CA (2000) The internal structure of mitochondria. Trends Biochem Sci 25:319-24.
  2. Cogliati S, Frezza C, Soriano ME, Varanita T, Quintana-Cabrera R, Corrado M, Cipolat S, Costa V, Casarin A, Gomes LC, Perales-Clemente E, Salviati L, Fernandez-Silva P, Enriquez JA, and Scorrano L (2013) Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency. Cell 155:160-71.
  3. Scorrano L, Ashiya M, Buttle K, Weiler S, Oakes SA, Mannella CA, Korsmeyer SJ (2002) A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. Dev Cell 2:55-67.