According to the endosymbiont theory a prokaryote invaded the primordial eukaryote. Over time this prokaryote was coopted to perform key metabolic functions for the cell and became what we now know to be the mitochondrium. This integration of an organism into the primordial eukaryotic cell required that communication evolved between the eukaryotic nucleus and the mitochondrial ancestor. We are interested in the interactions that evolved. Did one entity learn the language of the other or did they resort to a more primitive form of communication – a chemical language based on metabolites and chemical signaling molecules?
By challenging cells with various mitochondrial stresses we have begun to catalogue the nuclear transcriptional responses to various mitochondrial defects. Through this strategy we identified a new role for the multi drug resistance response, a cellular response pathway best known for being a major cause of chemotherapy failure and anti-microbial therapy resistance (Figure 1).
This pathway is activated in response to mitochondrial import defects and protects the organelle when import is impaired. Currently, we are investigating the molecular signals that elicit the mitochondrial import defect response and how this response protects mitochondria.
Ensuring that a cell has the right number of mitochondria to support its metabolic and biosynthetic needs is critical. Because mitochondrial DNA is essential for mitochondrial function, it is our hypothesis that mitochondrial number is determined by mitochondrial DNA copy number. We therefore study the control of mitochondrial DNA replication. We conduct these studies in budding yeast focusing on a predatory mitochondrial mutant known as hypersuppressive petite. This mitochondrial mutant quickly eliminates wild-type mitochondrial DNA when yeast cells harboring this mitochondrial mutant are mated to cells harboring wild-type mitochondria.
Our analyses of nuclear responses to mitochondrial stresses indicate that the relationship between the nucleus and mitochondrial compartment is still evolving. We must thus reevaluate our view of mitochondria. Rather than considering mitochondria fully integrated into the eukaryotic cell, we must think about the nuclear - mitochondrial relationship as a continuous battle. The nucleus’ goal is total control and exploitation - the mitochondrium still wants to escape this exploitive relationship. Understanding what battles are fought within our cells will provide key insights into the functions of mitochondria and how symbiotic relationships evolve.