Insulin resistance is the main defect leading to islet beta cell dysfunction and hyperglycemia in type 2 diabetes. Despite much effort the mechanism(s) of insulin resistance is/are not known. Mitochondria play a critical role in the cell to ensure energy levels are at the appropriate level.  Studies have shown that mitochondrial dysfunction is associated with and may well contribute to insulin resistance in diabetes. UBL-5 is an ubiquitin-like protein that was first discovered in the obese Israeli sand rat, associated with weight gain. Subsequently it has been shown that UBL-5 is involved in the mitochondrial stress response to ensure that chaperone proteins are transcribed to relieve the ensuing stress.  To further explore the role of UBL-5 in mitochondrial metabolism, we generated a tamoxifen-inducible and liver-specific UBL-5 knockout mouse.  Mice with liver-specific deletion of UBL-5 have a severe liver phenotype, with hepatic enzymes being 2-3 orders of magnitude higher than normal and die within 12 days following tamoxifen-induction.  Histological examination of the liver revealed multiple derangements including severe and diffuse multifocal hepatocellular necrosis, prominent cellular debris and angiectasi, multifocal hemorrhage, vacuolasion and shrunken hepatocytes, hypereosinophilic cytoplasm and nuclear pyknosis or karyorrhexis. Gene expression profiling of the liver showed that in KO mice the Ddit3 gene (which encodes CHOP) was reduced, while the expression of the UPR^mt genes (including Clpp, Hspd1 and Hspa9) were not different to control mice, suggesting the possible involvement of other biochemical pathway in the liver failure of the UBL-5 KO mice. In conclusion, liver-specific deletion of the mitochondrial stress response gene UBL-5 in adult mice leads to hepatic failure and early death.  This study provides the first evidence for a critical role for UBL-5 in hepatic function.