Understanding the Molecular Mechanisms of Mitochondrial Disease

In a recent WCMR Science Seminar, we heard from PhD student Yasmin Tang about her research funded by The Lily Foundation that aims to understand the molecular mechanisms of mitochondrial disease and dysfunction. Read on to find out more.

Mitochondrial disease is caused by genetic defects in genes that make proteins responsible for maintaining our mitochondria and allowing them to function. These proteins are important given the role of mitochondria as the main energy suppliers within the body’s cells. Our research interest is the identification of novel genetic changes that lead to mitochondrial disease and dysfunction using a technique called whole exome sequencing (WES). Once these genetic changes have been identified, further experimental studies are needed to understand the underlying disease mechanisms.

In one of my projects, I investigated genetic defects in the SLC25A26 gene identified by WES in two unrelated patients. Diagnostic assessments of patient muscle biopsies showed that essential components of the OXPHOS energy chain within the mitochondria were impaired. In addition, bioinformatics data suggested involvement of the SLC25A26 protein in the regulation of mitochondrial function. By carrying out protein analysis, the impact of these genetic changes on SLC25A26 protein levels and the levels and assembly of OXPHOS protein complexes were verified. When combined with animal model research performed by our collaborators, these findings confirmed the molecular mechanism was linked to impairment of SLC25A26, which is essential for the cellular energy supply through mitochondrial OXPHOS function.

Through this study, we confirmed that genetic changes in SLC25A26 lead to mild, late-onset mitochondrial disease and were able to demonstrate the pathological mechanisms involved. WES analysis of individuals with suspected mitochondrial disease continues to expand the repertoire of known mitochondrial disease-causing gene defects. This work supports genetic diagnosis of patients and opens up potential reproductive options for at-risk families. Further studies using different experimental approaches will allow us to uncover other disease mechanisms. This is important as better understanding of disease mechanisms could accelerate the progress of developing curative treatments for mitochondrial disease and dysfunction.

The study was published in the journal Human Molecular Genetics and can be found here.