As we continue our Wellcome Centre for Mitochondrial Research (WCMR) science seminar series for 2022-23, we were delighted to hear from Dr Valeria Di Leo and PhD student John Meyrick about their projects that highlight the diverse research themes across our Centre all aiming to transform the lives of those with mitochondrial disease and dysfunction. Read on to find out more.
Mitochondrial dysfunction in neuromuscular disorders by Valeria Di Leo.
Mitochondrial myopathy and myotonic dystrophy type 1 are two of the most common adult onset neuromuscular disorders for which there are currently no cures. Although both diseases present with symptoms that can affect any part of the body, skeletal muscle is usually the most affected tissue. Skeletal muscle tissue requires huge amounts of energy to contract and this is primarily produced by mitochondria. When the mitochondria do not function properly, muscular weakness occurs and patients may struggle to perform daily tasks such as walking or climbing stairs.
Over the last decade, exercise intervention has been investigated has an accessible and potential low-cost approach to improve symptoms in neuromuscular disorders. In particular, the WCMR and the Interdisciplinary Research Group on Neuromuscular Diseases (Université du Québec à Chicoutimi, Canada) investigated the benefits of a resistance exercise training programme in individuals with mitochondrial myopathy and myotonic dystrophy type 1. Participants performed supervised exercise sessions in the gym which involved lifting weights with their legs. Skeletal muscle biopsies were collected before and after exercise training from their legs (quadriceps) in order to investigate any changes triggered by resistance exercise training.
After exercise training, we observed that all individuals with mitochondrial myopathy displayed an increase in levels of one structure directly linked to the production of energy within mitochondria (COX1). Individuals with myotonic dystrophy type 1 displayed the same increase in COX1 and/or the increase of another structure involved in energy production within mitochondria (Ndufb8). It is important to highlight that individuals from both groups responded to exercise training in a “personalised” way. However, after exercise training we could see beneficial effects in those with both mitochondrial myopathy and myotonic dystrophy type 1, suggesting that resistance exercise training could be used to improve quality of life and physical performance of people with these conditions.
In individuals with mitochondrial myopathy, we identified what triggers the reprogramming of skeletal muscle after resistance exercise training. To further understand this process and to look for a drug that could mimic the benefits of resistance exercise, our future goal is to reproduce skeletal muscle from mitochondrial myopathy patients on a chip (3D muscle on chip). In collaboration with the Institute for Bioengineering of Catalonia (Spain), we will study whether the 3D muscle on chip resembles what we observe in patient tissue and subsequently screen some of the promising compounds identified from our team in order to find a drug that may treat mitochondrial myopathy.
Deciphering a mitoribosomal quality control machinery by Jonathan Meyrick.
Mitochondria are essential in providing our cells with energy. In this role, the proteins in our mitochondria need to be made correctly. Unlike other parts of the cell, mitochondria are able to make some of the necessary proteins using the mitochondrial DNA they possess. It is important that these proteins are made correctly and in a strictly controlled manner. Unfortunately, little is known about the protein machinery involved in this quality control, meaning current research is limited.
For some patients, variants in their mitochondrial DNA cause stress because the machinery which quality controls the making of their proteins becomes ‘over-worked’. This alone can cause symptoms, while in other patients, faulty quality control proteins themselves can cause disease.
As part of my work, I use antibiotics, in combination with common lab techniques to identify and study proteins that may be involved in quality control. Through understanding a hierarchy of this quality control machinery, and how these proteins interact, we hope to better understand disease pathology and advance research into curing these devastating mitochondrial diseases and pathology.