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.