Inside the light-sensitive cells of the retina, energy-producing mitochondria are strapped to the cell’s outer membrane by tiny tethers—and no one knows why. This project aims to solve that mystery. Photoreceptors and brain neurons demand enormous amounts of energy, and defects in mitochondria are already linked to visual and neurological disorders. Yet the specialised arrangement of mitochondria pressed against the plasma membrane, and the tethers that hold them there, has never been explained. The researchers will extract and identify the proteins that make up these tethers, image their three-dimensional structure using cryo-electron tomography, and then disrupt mitochondrial positioning in zebrafish to see how vision and cell health change over time. This is fundamental science. There is no immediate clinical application. But understanding how mitochondria are positioned and anchored in high-energy cells could eventually reveal why mitochondrial defects cause specific diseases—and point toward targets for future therapies. Similar work on mitochondrial contact sites has already reshaped our understanding of cellular metabolism and disease.
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Mitochondria are structures within cells that provide energy essential for life of many organisms including humans. Within most cells they are scattered and form a network with some of the other cellular structures nearby that they are in contact with (contact sites). As the light detecting photoreceptors within the retina and brain neurons require large amounts of energy, defects in mitochondrial have been associated with many diseases including visual and neurological disorders. Photoreceptors and neurons have recently been found to have specialised positioning of mitochondria, as they run alongside mitochondria from neighbouring cells and are in contact with the membrane that encases the cell (plasma membrane). This also includes structures called tethers that attach the mitochondria to the plasma membrane to hold them in place. Both the role of this arrangement of the mitochondria and the tethers is yet to be established. The attachment of the mitochondria to the plasma membrane will have evolved to suit a specialised role within these cells. To better understand this role and how it may relate to mitochondrial disease, the aim of this project is to identify what is controlling this specialised mitochondrial arrangement and to see what happens when the positioning of mitochondria is disrupted within these cells. To achieve this, we will extract and identify anything within the cell that is positioned between the mitochondria and the plasma membrane. By analysing these samples, we will be able to find out what these tethers are made up of and some of the components involved in positioning the mitochondria. We will study the structure of the tethers by examining high detailed three-dimensional images made using a technique called cryo-electron tomography. Finally, we will examine zebrafish that have altered positioning of the mitochondria within photoreceptors and neurons. Vision will be checked at different ages to determine how it is affected and using a range of microscopy methods eyes will be examined to determine the health of the cells. All together these experiments will provide important insight into the components and structure of the tethers and the role of this connection between mitochondria and the plasma membrane. These findings will be essential to understand how these features are linked to mitochondria function and possibly disease, paving the way for future studies.
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