SENS Research Foundation Research Center
Principal Investigator: Amutha Boominathan
Research Team: Nana Abena Anti, David Begelman, Bhavna Dixit, Caitlin Lewis, Sanjana Saravanan
Mitochondria are the tiny cellular “power plants” in our cells, which take energy from our food and convert it into a form that can be used to power the cell’s energy-intensive processes. Unfortunately, like actual power plants, they generate waste – in this case called free radicals, which damage mitochondrial DNA (mtDNA) over time. As a result, some cells become burdened by these dysfunctional mitochondria and can accumulate in the body as we age. These damaged cells in turn export toxic molecules to far-flung tissues, contributing to Parkinson’s disease, age-related muscle dysfunction, and other conditions.
The MitoSENS goal is to engineer a solution to the accumulation of cells with these mutation-bearing mitochondria via allotopic expression. Allotopic expression involves placing “backup copies” of all the protein-coding genes of the mtDNA in the cell’s nucleus. From this “safe harbor,” the copied genes can then direct the cell’s machinery to produce engineered versions of the missing mitochondrial proteins and deliver them to the correct location. With their full complement of proteins restored, mitochondria can resume producing energy normally – despite lacking functional copies of these genes to produce them on their own.
In 2019, the MitoSENS team achieved a major breakthrough in successfully demonstrating transient allotopic expression for all 13 mtDNA genes. This work was recently published in Redox Biology, 30 (2020) 101429. Several of these genes can be expressed stably and the team was further able to demonstrate a functional utility for these exogenous proteins in rescuing patient cell lines with specific mutations in the mtDNA genes ATP8, ATP6, and ND1 (Nucleic Acids Res. 44(19) 2016; 9342-9357 and Redox Biology 30 (2020) 101429).
Our current efforts are focused on validating this strategy in rescuing some of the more common inherited disease conditions observed as a result of mutations to mtDNA, such as Leber’s Hereditary Optic Neuropathy (LHON) and Leigh’s syndrome. We are also exploring alternative strategies and software based prediction models to optimize the expression of all 13 mtDNA genes and the transport and integration of their corresponding proteins into the mitochondria.
The MitoSENS team also has ongoing experiments to demonstrate efficacy in living, breathing mice – specifically, a transgenic ATP8 mouse derived from the Maximally Modifiable Mice (MMM) created through the SENS Research Foundation-funded work at Applied StemCell. The new MMM-derived mouse model will have the allotopic ATP8 copy engineered into their nuclear genomes but will inherit functionally compromised mitochondria (and thus mitochondrial DNA) from a cross with FVB mice, which have a specific mutation in the mitochondrial ATP8 gene. This work is being done in collaboration with the Brand lab at the Buck Institute and will include biochemical and behavioral assays to evaluate if the allotopically expressed ATP8 gene can rescue the phenotype.