Mortalin (GRP75, HSPA9A), a heat shock protein (HSP), regulates a wide range of cellular processes, including cell survival, growth, and metabolism. The regulatory functions of mortalin are mediated through a diverse set of protein partners associated with different cellular compartments, which allows mortalin to perform critical functions under physiological conditions, including mitochondrial protein quality control. However, alteration of mortalin’s activities, its abnormal subcellular compartmentalization, and its protein partners turn mortalin into a disease-driving protein in different pathological conditions, including cancers. Here, mortalin’s contributions to tumorigenic pathways are explained. Pathology information based on mortalin’s RNA expression extracted from The Cancer Genome Atlas (TCGA) transcriptomic database indicates that mortalin has an independent prognostic value in common tumors, including lung, breast, and colorectal cancer (CRC). Subsequently, the binding partners of mortalin reported in different cellular models, from yeast to mammalian cells, and its regulation by post-translational modifications are discussed. Finally, we focus on colorectal cancer and discuss how mortalin and its tumorigenic downstream protein targets are regulated by a ubiquitin-like protein through the 26S proteasomal degradation machinery. A broader understanding of the function of mortalin and its positive and negative regulation in the formation and progression of human diseases, particularly cancer, is essential for developing new strategies to treat a diverse set of human diseases critically associated with dysregulated mortalin.

Defects in the activity of the proteasome or its regulators are linked to several pathologies including neurodegenerative diseases. We hypothesize that proteasome heterogeneity and its selective partners vary across brain regions and have a large impact on proteasomal catalytic activities. Using neuronal cell cultures and brain tissues obtained from mice, we compared proteasomal activities from two distinct brain regions affected in neurodegenerative diseases, the striatum and the hippocampus. The results indicated that proteasome activities and their responses to proteasome inhibitors are determined by their subcellular localizations and their brain regions. Using a iodixanol gradient fractionation method, proteasome complexes were isolated, followed by proteomic analysis for proteasomal interaction partners. Proteomic results revealed gamma enolase (ENO2), a known proteasome partner, has more a nity to proteasome complexes puri ed from the striatum than to those from the hippocampus. These results highlight a potential key role for non-proteasomal partners of proteasome regarding the diverse activities of the proteasome complex recorded in several brain regions.

Defects in the activity of the proteasome or its regulators are linked to several pathologies including neurodegenerative diseases. We hypothesize that proteasome heterogeneity and its selective partners vary across brain regions and have a large impact on proteasomal catalytic activities. Using neuronal cell cultures and brain tissues obtained from mice, we compared proteasomal activities from two distinct brain regions affected in neurodegenerative diseases, the striatum and the hippocampus. The results indicated that proteasome activities and their responses to proteasome inhibitors are determined by their subcellular localizations and their brain regions. Using a iodixanol gradient fractionation method, proteasome complexes were isolated, followed by proteomic analysis for proteasomal interaction partners. Proteomic results revealed gamma enolase (ENO2), a known proteasome partner, has more affinity to proteasome complexes purified from the striatum than to those from the hippocampus. These results highlight a potential key role for non-proteasomal partners of proteasome regarding the diverse activities of the proteasome complex recorded in several brain regions.