Mapping the movements of the mitochondrial ADP/ATP carrier

Mitochondria generate energy for the body by making ATP (adenine triphosphate) from ADP (adenine diphosphate). For this to happen cells must shuttle ADP from the cell cytoplasm into the mitochondria through the membrane of the mitochondria. Similarly, once the ATP has been made it needs to be taken to other parts of the cell for use in chemical reactions. There is just one problem – ATP and ADP cannot travel through the inner mitochondrial membrane but instead travels via a carrier imbedded in the membrane called the mitochondrial ADP/ATP carrier. “Every day, this carrier transports our own body weight in ADP and ATP” says Dr. Ruprecht in his paper which investigates the precise molecular mechanisms of the carrier. 

 

Carrier molecules, like the mitochondrial ADP/ATP carrier, change shape in order to transport their cargo from one side of the membrane to the other. For the ADP/ATP carrier size matters. Compared to ADP and ATP the membrane protein is small, and therefore has to change significantly to allow passage through from one side to another. The carrier changes between two states; the cytoplasmic open state (for which the structure was already known) and the matrix open state. To understand how the carrier changed between states researchers first solved the 3D structure of the matrix open state.


Studying the 3D structure of the carrier requires a stable crystal form. The researchers were able to create crystals of the m state ATP/ADP with the help of a nanobody, the part of an antibody that binds to another molecule, prepared at Instruct-BE. X-ray diffraction data was then collected to reveal the 3D structure of the carrier molecule. 


Figure 7C-G from the paper showing the proposed transport mechanism of the mitochondrial ADP/ATP carrier in the cytoplasmic state (c-state) and the matrix state (m-state) (Image used under Creative Commons Attribution License CC BY 4.0 DOI:https://doi.org/10.1016/j.cell.2018.11.025)


Dr. Ruprecht from the MRC Mitochondrial Biology Unit and his colleagues have also deciphered the changes that happen to the mitochondrial ADP/ATP carrier during the transport of molecules using a combination of techniques including technology at The Diamond Light Source (an Instruct research site) in the UK. 

 

Locking the carrier in one position using inhibitors allowed the team to investigate the shape of different sections of the carrier molecule. The results show that sections of the carrier rotate to let ADP and ATP through. The team suggests that mitochondrial carriers for other molecules are likely to use the same mechanism.


Click here for more information about nanobodies at Instruct. 


Full paper: Ruprecht, J.J., et al. (2019) The Molecular Mechanism of Transport by the Mitochondrial ADP/ATP Carrier, Cell 176: 435