Scientists have made a significant discovery about genetic mutations linked to a wide range of diseases, including cancer, which could pave the way for better treatments.

Dr Rhiannon Lloyd and Dr John McGeehan, of the University of Portsmouth, have created the first 3D disease map of mitochondrial proteins – miniature machines that assemble to form energy-producing ‘batteries’ in the human body.

Their map will allow doctors and researchers to make better diagnoses and develop better treatments of patients affected by mitochondrial disease. It also opens the possibility of scientists one day being able to build patient-specific maps identifying precisely what is happening at molecular level.

Dr Lloyd said: “Our bodies contain many thousand miniature energy-producing ‘batteries’ known as mitochondria.

“Defective mitochondria are associated with a range of serious human diseases, including cancer.

“The UK government has recently backed the use of three-parent IVF technologies to help those parents who are carriers to have healthy children, but research is urgently required to identify how these diseases occur in the first place.

“This 3D map paves the way for scientists and drug developers to be given for the first time a window to what is happening at molecular level in some diseases.”

Mitochondria have their own DNA which contains the genetic information to make vital energy-producing proteins and it is small defects, or mutations, in this DNA which can cause disease.

Despite the continuing discovery of more and more of these mutations, it remains fundamentally difficult to tell which ones are important in disease.

Dr Lloyd and Dr McGeehan have developed a strategy to visualise these mutations in 3D inside the mitochondrial proteins, allowing them to predict each mutations’ importance in a wide-range of diseases.

Dr McGeehan said: “Almost 100 mutations associated with diseases were analysed in 3D and categorised based on their location within the mitochondrial proteins (Picture 2). We created a comprehensive 3D map that led to the significant discovery of a new category of disease-associated mutation.

“Current available tools for predicting disease are extremely useful but often give contradictory information when applied to mitochondrial mutations, falling short of the Holy Grail of telling clinicians how likely and how severe mitochondrial  diseases will be from the results of a straightforward genetic test.”

The energy-producing components of mitochondria are made of multiple different proteins, and the new class of mutation was found at the interfaces between the different proteins, potentially disrupting their interaction and causing disease (Picture 2).

Dr Lloyd said: “This type of mutation is not easily detected using existing strategies but could provide a molecular basis for several unexplained disease cases, information that could help clinicians in both diagnosis and treatment in the future.”

This new strategy is now being implemented in the University of Portsmouth’s neuro-oncology group (LINK) to predict the importance of mitochondrial mutations found in brain tumours, particularly in patients with Gliblastoma multiforme. This is the most common primary brain tumour and a disease that carries a dismal prognosis in both children and adults (Picture 3).

Professor Geoff Pilkington, who heads this group, said: “The over-arching aim of this work is to identify specific mitochondrial mutations that can be used as biomarkers to predict the development, progression and chemosensitivity, leading to improved diagnoses and prognoses for of patients unfortunate enough to develop brain tumours.”

Dr Lloyd’s and Dr McGeehan’s research was part-funded by the University of Portsmouth’s research development fund and is published in the international journal PLOS ONE.

Source: Portsmouth University