Project 1: The role of mitochondrial stress in liver aging and cancer progression and intervention via oxidative mitohormesis

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PROJECT SUMMARY – PROJECT 1 Mitochondrial dysfunction, oxidative stress and inflammation are hallmarks of aging and cancer, but crosstalk between these processes are not well understood. Mitochondria are complex and dynamic organelles at the nexus of cellular energy metabolism, redox balance, and critical signaling pathways that regulate both cell physiology and cell death. In cancer cells, mitochondria are remodeled in many ways to promote metabolic states that support cell proliferation and prevent cell death. This is accompanied by changes in cellular redox status due to increased reactive oxygen species production that can promote oxidative stress and genomic instability (of both nuclear and mitochondrial DNA, mtDNA). Similarly, reduced mitochondrial respiratory capacity, increased ROS production, and genomic instability are hallmarks of the normal aging process. Since aging is a major risk factor for most adult cancers, the major premise of Project 1 of the program is that age-related changes in mitochondrial dynamics, function and signaling underlie cancer susceptibility with aging. Furthermore, based on our preliminary and published results, we propose that, in addition to the mitochondrial changes indicated above, mtDNA-mediated inflammatory pathways are a key feature of aging and age-related cancer initiation. We also hypothesize that a novel form of adaptive cellular signaling, called “oxidative mitohormesis,” will prevent or delay age-related liver dysfunction and cancer initiation. Project 1 has three specific aims. Aim 1 is to determine the role of age-related mitochondrial dysfunction in mtDNA-mediated inflammatory signaling and its contribution to liver cancer. Aim 2 is to determine the contribution of the mtDNA-cGAS-Sting pathway to liver aging and age- dependent liver cancer susceptibility. And, Aim 3 is to test oxidative mitohormesis as an intervention for liver aging and liver cancer. To accomplish these aims we will use a combination of innovative mouse models in which we can generate specific gene knock-outs or initiate liver cancer at different ages. In addition, we can induce mitohormetic responses by inducible and reversible knock-down of the mitochondrial antioxidant enzyme, SOD2 (iSOD2 mice). Finally, as part of common effort by all four labs in the program, who have different, but complimentary expertise and hypotheses about the role of inflammation in aging and cancer, we will assess a multitude of phenotypes (gene expression, chromatin remodeling, immune cell infiltration and activity, inflammation, mitochondrial dysfunction and metabolism) in normal aging liver and in an age-dependent Pten knock-out model of liver cancer. Project 1 will contribute expertise in mitochondria, mtDNA-mediated inflammation, and adaptive mitochondrial stress signaling to this concerted effort to understand the age- dependence of liver cancer. Key findings will be translated into normal and NALFD liver samples from humans of different ages.