Heterogeneity of Mitochondrial Redox State in Premalignant Pancreas in a PTEN Null Transgenic Mouse Model

Abstract

Pancreas-specific deletion of PTEN in mice revealed progressive premalignant lesions such as ductal metaplasia with infrequent malignant transformation. In this study, we aimed at evaluating the mitochondrial redox state of the metaplastic pancreas in a pancreas-specific PTEN null transgenic mouse model. The two intrinsic fluorophores, reduced nicotinamide adenine dinucleotide (NADH) and oxidized flavoproteins (Fp) such as flavin adenine dinucleotide (FAD), in the respiratory chain in mitochondria are sensitive indicators of mitochondrial redox states and have been applied to the studies of mitochondrial function with energy-linked processes. The redox ratio, Fp/(Fp+NADH) provides a sensitive index of mitochondrial redox state. We have obtained optical images of the in vivomitochondrial redox states of the snapfrozen pancreases from pancreas-specific PTEN null mice (Pdx1-Cre;PTEN^lox/lox, N=3) and the controls (PTEN^lox/lox, N=3) using the redox scanner at low temperature. The results showed high spatial heterogeneity ofmitochondrial redox state in the mutated pancreases with hot spots of much higher Fp redox ratios whereas the normal ones, were relatively homogenous. The cystic dilation regions in the metaplastic pancreases showed little to no NADH or Fp signal. Histological analysis confirmed no cells existed in these regions. It is the first time that the in vivo mitochondrial redox states of the metaplastic mouse pancreas were optically imaged. Our previous results on human melanoma and breast cancer mouse xenografts have shown that mitochondrial redox state quantitatively correlates with cancer metastatic potential. The more oxidative mitochondrial redox state (higher Fp redox ratio) corresponded to the higher metastatic potential of the tumors. As mitochondrial redox state imbalance is associated with abnormal mitochondrial function, and redox state mediates the generation of reactive oxygen species and many signal transduction pathways, this research may provide insights for studying basic biology and developing early diagnostic imaging biomarkers for pancreatic cancer.