The SENS Research Foundation is raising funds to research finding a cure for mitochondrial DNA diseases.

Following the success of its first experiment.com campaign, which was raising money to identify therapeutics that reduce senescent cell accumulation and extend healthspan, the SENS Research Foundation has announced the next funding project.

Last month, we covered the fundraiser for Dr Abdelhadi Rebbaa’s research into the discovery and testing of novel senolytic molecules, which would back into his discovery of potential anti-senescence therapeutics. SRF has confirmed that this campaign is now fully funded.

Now SENS Research Foundation has launched its second experiment.com campaign for Dr Amutha Boominathan’s project Finding a cure for mitochondrial DNA diseases through COX2 variations to restore cell function, hoping to raise $8,000 over 45 days, with the campaign coming to an end next month, on 30th August. Dr Boominathan is head of the MitoSENS program at SENS Research Foundation.

Longevity.Technology: Interest in mitochondrial DNA as both a determinant of aging and age-associated diseases has been growing in recent years, with various studies demonstrating evidence that mitochondrial DNA can play a significant role in age-related pathology. Mitochondrial dysfunction has long been recognized as one of the hallmarks of aging, and inherited and acquired mutations in the mitochondrial DNA can lead to several debilitating diseases, including blindness, neurodegeneration and sarcopenia.

Gene therapy can be a viable strategy to alleviate such diseases, and Dr Boominathan’s project proposes to use it to rescue mitochondrial function – in a nutshell, her project aims to reboot the cell’s power plant and restore its ability to produce cellular energy.

Initially evolving from ancient bacteria, mitochondria are tiny organelles in our cells that have a big role to play; they are responsible for the production of cellular energy (ATP) and other vital functions. Mitochondria are unique among animal organelles because their genome distinct from the nucleus, and the human mitochondrial genome contains 13 genes essential to oxidative phosphorylation (OxPHOS).

However, mitochondrial DNA is highly prone to mutation due to a variety of factors which include a combined lack of protective histones, reactive oxygen species generation in the inner membrane and limited repair mechanisms [1]. These mutations result in several pathologies, and SRF is on a mission to identify gene therapy approaches to address these mutations.

The COX2 gene is a core component of Complex IV in the OxPHOS relay. Mutations in this gene are associated with C IV deficiency affecting a critical step in the oxidation of cytochrome C using molecular oxygen.

Boominathan’s project hopes to identify variants of Cytochrome oxidase subunit 2 (COX2) and validate its utility in rescuing function in a model cell line derived from a multi-system disorder and COX2 deficient patient. To put it simply, the project aims to reboot the cell’s power plant and restore its ability to produce cellular energy.

COXsure

Boominathan’s lab has successfully produced proteins for all 13 genes found in mitochondria by allotopic expression, but only one (ATP8) has successfully restored function in a disease-model cell line. That natural evolution has already transferred >1000 genes from mitochondrial DNA to the nucleus.

The project’s goal is to find variants of the COX2 gene that can help cells function properly by mimicking the natural evolutionary process. Results from such an experiment would not only be a significant step towards efficacious COX2 gene therapy but would also provide key insights into the genetic changes necessary for successful allotopic expression of all mitochondrial genes.

Making it happen

Boominathan and her team propose to generate >1 million variants for the COX2 gene using error-prone PCR similar to a study performed in yeasts and test these variants in rescuing oxidative phosphorylation, a function that is crucial for ATP production in cells.

The nutrients that we consume are metabolized to CO2 and high-energy electron donors that further combine with oxygen to convert ADP to ATP. The team plan to test this in a human model cell line that is lacking the COX2 protein – this cell line is unable to grow in nutrient medium restrictive for oxidative phosphorylation. Upon placing the variants in such a medium, only cells that are capable of performing OxPHOS can survive meaning that such a screen would allow the researchers to identify functional variants of the COX2 gene for further analysis.

It is hoped that successful funding of this project will help pave the way to treat myopathy, infertility, and coronary artery disease, among others due to COX2 mutations.

Find out more or back the project HERE.

[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3757997/