At its most basic level, cancer is a disease of unregulated cell division and growth. While many molecular pathways participate in cell division, it is primarily regulated by energy production. Most cellular energy is generated in the mitochondria. Mitochondrial dysfunction is correlated with several types of cancer. However, mitochondria perform several additional functions, including synthesis, degradation, fission/fusion, and signaling. Thus, before we can understand how mitochondrial dysfunction contributes to cancer development, we need to better understand mitochondrial function. The overall objective of the Hirschey Lab is to generate a mitochondrial map describing the interaction between mitochondrial genes and function. Using this map, we will better understand specifically which pathways are dysfunctional in cancers and will then identify new targets which could be exploited for cancer therapy.

Mitochondria are specialized sub-cellular organelles for producing energy, and contain their own DNA encoding crucial energy-generating proteins. Mitochondrial DNA (mtDNA) is particularly susceptible to damage, both by DNA replication/reading errors and reactive oxygen species (ROS)-induced damage. After damage occurs, impaired mitochondria send a signal for damaged mtDNA to be either repaired, or destroyed by mitophagy or apoptosis. However, if damaged mitochondria do not generate a signal, damage can go undetected and neither repair nor destruction would occur. Because a single cell contains approximately 1000 mitochondria, and each mitochondria contains between 1-10 copies of mtDNA, damage to a single mtDNA has a negligible effect on overall cellular function. However if mtDNA damage accumulates, with age for example, then mitochondrial function and energy production will decline. Fortunately, cells can produce energy outside the mitochondria by glycolysis. Although less efficient, glycolysis provides enough energy for cell survival. One of the byproducts of shifting metabolism outside the mitochondria towards glycolysis is an increase in lactate production. Since Warburg first demonstrated that cancer cells produce more lactate than normal cells in the 1920's, many scientists have sought to understand the mechanism of this metabolic switch and how energy metabolism is reprogrammed during cancer. Recent studies on stem cell proliferation and differentiation provide insight by showing that highly proliferative cells are predominantly glycolytic. However when a stem cell stops proliferating and begins to differentiate into specialized cell types, these cells are predominantly respiratory and generate energy in the mitochondria. Thus, the increased lactate levels observed by Warburg could be a signal of shifting metabolism and increasing proliferation. Taken together, this model proposes that cancer could be caused by cumulative mitochondrial damage, reduced mitochondrial function, leading ultimately to a compensatory shift in metabolism that drives cellular proliferation. If this model is correct, it follows that proper mitochondrial function is crucial for the balance between cell division and cell growth. Furthermore, some forms of cancer could be prevented or treated if mitochondrial function and the signals for mitochondrial damage were better understood.

We are testing this model and focusing specifically on how damaged mitochondrial proteins and mtDNA signal their distress, and how damage is removed within the mitochondria. Our premise is that this fundamental process can be described and used as a target for intervention to impact cancer prevention and treatment. The Hirschey Lab uses the power of systems biology to integrate several biochemical and cellular measurements to generate a map of mitochondrial function. Both biochemical and physiological data points are integrated into a network of functional relationships using several statistical models, including Bayesian statistics and machine learning. When completed, this network will be queried to identify the key machinery responsible for mitochondrial damage signaling and repair; ultimately these data will be made available online for researchers to use in their own experimental models.

Why build a mitochondrial network? In the near-term, our approach will integrate key features of mitochondria into a functional map using a combination of high-throughput biological measurements and statistically robust data integration. Finally, we will use this tool to identify the consequence of reduced mitochondrial function on cellular proliferation and vulnerabilities which could be exploited for cancer therapies. In the long-term, however, a more fundamental goal of this project is to apply a formal, systematic approach to biology, pioneered by engineers and mathematicians. While the one-gene-at-a-time approach has produced some results, cancer research still doesn't provide large-scale cancer therapeutics for patients. Building a network could make research in this area more meaningful and more productive. Building this tool will ultimately accelerate science.