Changes in gene expression after mitochondrial augmentation of mouse hematopoietic stem cells

Mitochondria, known as the powerhouse of the cell, have a plethora of diverse functions that explain why mitochondria are crucial for systemic health. Mitochondrial diseases, characterized by dysfunctional mitochondria, characteristically involve multiple systems. Unfortunately, there are limited treatment options, and these largely remain symptomatic.

Mitochondrial augmentation therapy (MAT) is an autologous cell therapy developed to treat patients with primary mitochondrial diseases. In MAT patient-derived hematopoietic stem and progenitor cells are enriched ex-vivo with healthy donor mitochondria and reinfused to the bloodstream. To date, we have treated six patients with mitochondrial deletion syndromes and preliminary data indicate safety and initial signs of efficacy in multiple organs, including muscle, brain, liver and kidney.

In order to determine the effect of MAT on gene expression, we utilized aging mice as a model for damage accumulation that can mimic systemic mitochondrial dysfunction. To this end, we have treated aged (15 month) C57BL/6 mice once with age-matched hematopoietic stem cells, either unmanipulated or augmented with mitochondria harvested from placentae of young C57BL/6 mice. A month after treatment, we compared the gene expression profile of age-dependent genes between the groups. We have shown that a single mitochondrial augmentation therapy treatment shifted the expression profile in several age-related genes to a ‘younger’ expression profile in several different tissues, such as brain and kidney. We are now designing techniques for tracking augmented mitochondria/cells in-vivo that will enable us to follow the biodistribution in different organs as one potential mechanism by which MAT can benefit organ function.