@article{Functions:2116,
      recid = {2116},
      author = {Springer, Maya Zafrir},
      title = {Functions of BNIP3 in Nutrient Stress Responses},
      publisher = {University of Chicago},
      school = {Ph.D.},
      address = {2019-12},
      pages = {143},
      abstract = {BNIP3 is a mitophagy receptor that targets mitochondria  for degradation at the autophagolysosome. By mediating  mitophagy, BNIP3 functions to decrease mitochondrial mass  as an adaptive response to stress, namely hypoxia and  nutrient starvation. This catabolic mechanism prevents the  accumulation of damaging reactive oxygen species that are  normally generated during mitochondrial respiration, thus  functioning to maintain a healthy pool of mitochondria  under nutrient stress. Evidence in the field has indicated  a prognostic role for BNIP3 in hematological malignancies  and cancers of the pancreas, breast, liver, colon, and  stomach, with epigenetic silencing or deletion of BNIP3  observed in progression to invasive carcinoma. Importantly,  loss of BNIP3 is associated with higher tumor grade, poor  prognosis, and resistance to chemotherapy. Findings from  our laboratory also support a tumor suppressor function for  BNIP3 in mouse models of breast cancer, pancreatic ductal  adenocarcinoma, and hepatocellular carcinoma. Work from our  laboratory has also established a critical housekeeping  function for BNIP3 in normal liver physiology and during  fasting, with implications for systemic metabolism under  nutrient deprivation. In addition to maintaining the  integrity of the mitochondria in hepatocytes, BNIP3 also  mediates downstream effects on oxygen consumption,  gluconeogenesis, and lipid metabolism. The critical  functions of BNIP3 in stress responses of the liver have  implications for metabolic diseases, such as obesity,  diabetes, steatohepatitis, and cancer.

The work in this  thesis expands our understanding of how BNIP3 impacts  cellular metabolism during nutrient stress to maintain  mitochondrial integrity and energetic homeostasis, with  implications for normal physiology and cancer. We describe  a previously unknown function for BNIP3 in suppressing the  nuclear transcription factor ATF4, the master regulator of  the amino acid biosynthesis response, in response to  nutrient starvation in the murine liver and human  hepatocellular carcinoma cells.  We demonstrate that this  requires the mitochondrial localization of ATF4 that is  dependent on BNIP3, which functions to limit ATF4 nuclear  localization and downstream transcriptional activities.  Furthermore, this mechanism involves the tri-molecular  interaction of ATF4, BNIP3, and LC3 at mitophagosomes and  the turnover of ATF4 by mitophagy. Our studies reveal that  this novel interaction bears functional consequences for  mitophagy, mitochondrial stress responses, cellular  metabolism, and cell growth. Together, these results  establish an integral role for BNIP3 in regulating the  amino acid stress response through a novel mitochondrial  function for ATF4.},
      url = {http://knowledge.uchicago.edu/record/2116},
      doi = {https://doi.org/10.6082/uchicago.2116},
}