Cupo Research

Mitochondria are required for cellular energy production, yet the very process of respiration is damaging to cells, mitochondria, and molecules such as protein and DNA. In addition to the physiological stress of respiration, genetic mutations and environmental factors can drive mitochondrial damage. The Cupo Lab is interested in how mitochondria resolve stress via cellular signaling pathways, organellar stress responses, and protein quality control machinery using a variety of cell biology and biochemical techniques. Many components of the mitochondrial quality control machinery are mutated in disease; insufficient stress responses can lead to a sensitivity to apoptosis and drive neurodegenerative disorders, whereas excess mitochondrial quality control capacity can contribute to oncogenesis and drive chemoresistance.

Our lab is primarily interested in protein folding stress. All proteins must take on tertiary and quaternary structure as defined by their primary amino acid sequence. However, protein folding is fraught with challenges. Mitochondria present a particularly challenging protein folding environment. Protein quality control machinery, such as chaperones, proteases, and disaggregases assist with the folding, unfolding, disaggregation, and degradation of proteins. Additionally, protein quality control machinery can play regulatory roles in mitochondrial signaling pathways. Some questions we seek to answer include: How do the various mitochondrial protein quality control machinery recognize substrates? How do substrate-interactions regulate mitochondrial biology? How does disease dysregulate substrate interactions and the consequent physiology?

Mitochondrial DNA (mtDNA) is essential for cellular energy production as it encodes 13 core components of the mitochondrial respiratory complexes. Unlike the nucleus, there are thousands of copies of mtDNA per cell. Additionally, mtDNA faces special challenges as compared to nuclear DNA as mtDNA is localized to the same compartment as the major reactive oxygen species production sites in the cell. However, mitochondria lack many of the key repair pathways that are used by the nucleus to repair defective DNA. Thus, removing damaged mtDNA is key in promoting cellular energy production. We seek to gain deeper understanding of the pathways and proteins involved in the elimination of damaged mtDNA.