Elucidating mito-cellular signaling to alleviate symptoms of mitochondrial disease

Mitochondrial diseases are a group of generally uncurable disorders with an often lethal outcome.

Because mitochondria are essential for efficient energy production, the symptoms of mitochondrial disease have been considered to stem from cellular energy deficiency.

However, emerging evidence rather links some mitochondrial disease symptoms to the chronic activation of pathways that signal mitochondrial defects to the rest of the cell — so-called retrograde signaling.

Accordingly, abrogation of retrograde signaling in animal models of mitochondrial disease eliminates some of the disease symptoms, highlighting the potential of retrograde signaling pathways as therapeutic targets.

Despite this clear medical relevance, the many complex signaling pathways that can mediate retrograde signaling following various mitochondrial defects is not comprehensively understood, impeding their use as targets for future treatment options.We have recently identified the Rho5 signaling pathway as a component of the retrograde signaling that follows the loss of the mitochondrial genome in Saccharomyces cerevisiae.

The purpose of this proposed project is to characterize the role of the Rho5 pathway in retrograde signaling in both yeast and human cells.

This work will uncover molecular-level details of the retrograde signaling triggered by mitochondrial DNA defects that is a potential target for the development of future treatment options.