University of Pittsburgh Cancer Institute (UPCI)

Mitochondria and Metabolism

Mitochondria in a Dividing Cell The mitochondrial apoptotic pathway is activated by many types of cellular stress, and when initiated, causes programmed death. One hallmark of cancer cells is their ability to overcome apoptotic signals of cell death. Metabolic changes are another hallmark of cancer, and the nature of cellular bioenergetics in tumor cells is an area of active research. MCCBP investigators are involved in studies of cellular metabolism, apoptosis, and mitochondrial physiology in normal and cancer cells.

Selected Publications

  • The role of bone marrow (BM) and BM-derived cells in radiation-induced acute gastrointestinal (GI) syndrome is controversial. Bone marrow transplantation (BMT), total body irradiation (TBI) and abdominal irradiation (ABI) models were used to demonstrate a very limited, if any, role of BM-derived cells in acute GI injury and recovery. Compared with WT BM recipients, mice receiving BM from radiation-resistant PUMA KO mice show no protection from crypt and villus injury or recovery after 15 or 12 Gy TBI, but have a significant survival benefit at 12 Gy TBI. PUMA KO BM significantly protects donor-derived pan-intestinal haematopoietic (CD45+) and endothelial (CD105+) cells after IR. PUMA KO BM fails to enhance animal survival or crypt regeneration in radiosensitive p21 KO-recipient mice. These findings clearly separate the effects of radiation on the intestinal epithelium from those on the BM and endothelial cells in dose-dependent acute radiation toxicity. (Leibowitz et. al., Nat Commun. 2014 Mar 18;5:3494.)
  • Re-expression of the Myc oncoprotein in myc-/- fibroblasts is accompanied by a gradual accumulation of mitochondrial biomass and by increases in membrane polarization and mitochondrial fusion. A correction of oxidative phosphorylation (OXPHOS) deficiency is also seen, although structural abnormalities in electron transport chain complexes (ETC) are not entirely normalized. Conversely, the down-regulation of Myc leads to a gradual decrease in mitochondrial mass and a more rapid loss of fusion and membrane potential. Increases in the levels of proteins specifically involved in mitochondrial fission and fusion support the idea that Myc affects mitochondrial mass by influencing both of these processes, albeit favoring the latter. The ETC defects that persist following Myc restoration may represent metabolic adaptations, as mitochondrial function is re-directed away from producing ATP to providing a source of metabolic precursors demanded by the transformed cell. (Graves et. al., PLoS One. 2012;7(5):e37699.)
  • The balance between apoptosis ("programmed cell death") and autophagy ("programmed cell survival") is important in tumor development and response to therapy. This study demonstrated that high mobility group box 1 (HMGB1) and p53 form a complex that regulates the balance between tumor cell death and survival. Knockout of p53 in HCT116 cells increases expression of cytosolic HMGB1 and induces autophagy. Conversely, knockout of HMGB1 in mouse embryonic fibroblasts increases p53 cytosolic localization and decreases autophagy. p53 is thus a negative regulator of the HMGB1/Beclin 1 complex, and HMGB1 promotes autophagy in the setting of diminished p53. HMGB1-mediated autophagy promotes tumor cell survival in the setting of p53-dependent processes. The HMGB1/p53 complex affects the cytoplasmic localization of the reciprocal binding partner, thereby regulating subsequent levels of autophagy and apoptosis. (Livesey et. al., Cancer Res. 2012 Apr 15;72(8):1996-2005.)

Members

Brodsky, Jeffrey, PhD
Biological Sciences
Stolz, Donna Beer, PhD
Cell Biology
Huard, Johnny, PhD
Orthopaedic Surgery
Tang, Daolin, MD, PhD
Surgery
Lee, Yong, PhD
Surgery
Thomas, Gary, PhD
Microbiology and Molecular Genetics
Prochownik, Edward, MD, PhD
Pediatrics (CHP)
Van Houten, Bennett, PhD
Pharmacology & Chemical Biology
Schatten, Gerald, PhD
Obstetrics, Gynecology & Reproductive Sciences
Yu, Jian, PhD
Pathology
Sobol, Robert, PhD
Pharmacology & Chemical Biology
Zhang, Lin, PhD
Pharmacology & Chemical Biology