Browsing by keyword "mitochondrial dysfunction"

Now showing items 1-2 of 2

    • Integrating the UPRmt into the mitochondrial maintenance network
      Fiorese, Christopher J.; Haynes, Cole M. (2017-06-01)
      Mitochondrial function is central to many different processes in the cell, from oxidative phosphorylation to the synthesis of iron-sulfur clusters. Therefore, mitochondrial dysfunction underlies a diverse array of diseases, from neurodegenerative diseases to cancer. Stress can be communicated to the cytosol and nucleus from the mitochondria through many different signals, and in response the cell can effect everything from transcriptional to post-transcriptional responses to protect the mitochondrial network. How these responses are coordinated have only recently begun to be understood. In this review, we explore how the cell maintains mitochondrial function, focusing on the mitochondrial unfolded protein response (UPRmt), a transcriptional response that can activate a wide array of programs to repair and restore mitochondrial function.

    • Kupffer Cell-Derived Tnf Triggers Cholangiocellular Tumorigenesis through JNK due to Chronic Mitochondrial Dysfunction and ROS
      Technische Universitat München; Davis, Roger J.; Heikenwalder, Mathias (2017-06-12)
      Intrahepatic cholangiocarcinoma (ICC) is a highly malignant, heterogeneous cancer with poor treatment options. We found that mitochondrial dysfunction and oxidative stress trigger a niche favoring cholangiocellular overgrowth and tumorigenesis. Liver damage, reactive oxygen species (ROS) and paracrine tumor necrosis factor (Tnf) from Kupffer cells caused JNK-mediated cholangiocellular proliferation and oncogenic transformation. Anti-oxidant treatment, Kupffer cell depletion, Tnfr1 deletion, or JNK inhibition reduced cholangiocellular pre-neoplastic lesions. Liver-specific JNK1/2 deletion led to tumor reduction and enhanced survival in Akt/Notch- or p53/Kras-induced ICC models. In human ICC, high Tnf expression near ICC lesions, cholangiocellular JNK-phosphorylation, and ROS accumulation in surrounding hepatocytes are present. Thus, Kupffer cell-derived Tnf favors cholangiocellular proliferation/differentiation and carcinogenesis. Targeting the ROS/Tnf/JNK axis may provide opportunities for ICC therapy.