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VIRTUAL CELL SIMULATIONS OF MITOCHONDRIAL ADENINE NUCLEOTIDE FLUXES: ROLE OF ORGANELLE MORPHOLOGY IN ENERGY OUTPUT I.I. Moraru1,
B.M. Slepchenko1, C.A. Mannella2 and L.M. Loew1
Mitochondria undergo dramatic changes in morphology when the level of respiratory activity changes. It is unclear whether transitions between the “orthodox” and “condensed” states directly regulate mitochondrial function. Recent 3D reconstructions from high voltage transmission electron micrographs provided new insights into cristae morphology, suggesting that concentration gradients may develop in the intra-cristae space. We used the Virtual Cell modeling system (http://nrcam.uchc.edu) to test this hypothesis. For [H+], both 2D and 3D simulations showed neither steady state nor dynamic gradients even at maximum pumping rates. Assuming the inner membrane as an equipotential surface, this suggests that the driving force of ATP synthesis is constant throughout the cristae invaginations. However, simulations suggested that significant gradients in adenine nucleotide concentrations, in particular ADP, might occur. When rate equations for the ATP/ADP antiporter and the F0F1 ATP synthase were included in the model, the system displayed a wide range of steady state spatial distributions in ADP concentrations, both within the matrix and the intra-cristae space in the simulations. This distribution was highly dependent on the number, size, and shape of intra-cristae sacs. Static and dynamic gradients in ADP concentrations were present, as high as 80% drops from cytosolic levels ([ADP]cristae < 10 µM). A surprising consequence of the observed results is that the “condensed” state, characteristic of highly active mitochondria, is energetically less efficient, having significant amounts of inner membrane surface working under conditions less favorable to ADP uptake and ATP export. However, this state appears to be much more responsive to large changes in energy demands by the cytosol. Additionally, simulations predict that changes in the shape of the cristae junctional area can induce fast changes in total energetic output at constant levels of respiratory substrate.
For further information contact...Carmen Mannella: carmen@wadsworth.org |
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