Following a recent presentation as part of our WCMR Science Seminar Series, Dr Iffath Ghouri provides an update on her research project that is aiming to identify small molecule therapeutics for mitochondrial disease. Read on to find out more.

There is no cure for mitochondrial disease and current treatment strategies focus on relieving symptoms and supportive therapy. Together with the other members of the WCMR Treatment Team, we are working to develop drugs that can improve mitochondrial function, leading to treatments that we hope will improve quality of life for those living with the condition. 

Our approach to drug discovery involves screening tens of thousands of compounds from small molecule libraries using a high throughput screening (HTS) assay. These compounds are derived from a number of sources, including microbial and plant extracts and synthetic compounds. The most promising looking compounds from the HTS assay (the “hit” compounds) are then tested on a range of assays that we use to determine how effective the identified hits are at improving mitochondrial function.  

The aim of my current work is to develop a functional assay that is physiologically relevant, which can show the effectiveness of a drug in a cell type that is severely affected by mitochondrial disease. This assay involves imaging calcium (Ca²⁺) using a Ca²⁺ sensitive fluorescent dye that allows us to measure the levels of Ca²⁺ inside the cell and how they change when we stimulate Ca²⁺ entry. The subsequent removal of Ca²⁺ from the cell requires energy derived from ATP, so if there is a problem with the ATP supply, Ca²⁺ handling is likely to be affected.  

We use nerve cells (neurons) that we differentiate from stem cells to perform this assay. These stem cells were derived from donated skin cells from a mitochondrial disease patient. There are two types of neuron; one containing a high level of mutated mitochondrial DNA (the disease line) and one with very low (or no) mutation present (the healthy control line). We can use these two types of neuron to identify if there is a difference in Ca²⁺ handling between diseased and healthy neurons, and also to see if the treatments we are developing are improving any deficiency in Ca²⁺ signalling. This would indicate whether the treatments are improving ATP supply and making a positive difference to the normal functioning of the neuron. 

Our aim is to use the Ca²⁺ imaging assay as a tool in the drug discovery process to help us take drugs forward to successful mitochondrial disease treatment.