The Role of Mortalin in Biology and Disease

Mortalin (encoded by HSPA9 and also called GRP75/PBP74) is a member of the heat shock protein (HSP) 70 family. Although mortalin was originally identified as the mitochondrial HSP70 mediating important mitochondrial processes, recent studies have substantially expanded our knowledge of the role of mortalin in previously unexpected subcellular compartments and in mediating previously unknown processes. Mortalin is altered either genetically or epigenetically in different diseases and plays an important role in the onset or progression of such diseases. For example, mortalin is often upregulated and mislocalized in cancer, facilitating multiple aspects of tumorigenesis, including tumor cell proliferation and survival, stemness, epithelial-mesenchymal transition, and angiogenesis. Mortalin mutations have also been identified in association with neurodegeneration. In addition, mortalin has been shown for its role in micropinocytosis, immune responses, and viral infection. Indeed, growing evidence suggests the significance of mortalin in regulating different diseases and cell physiological contexts. Therefore, it becomes necessary to review these findings and update our knowledge of this molecular chaperone.

This Research Topic aims to cover recent advances in the molecular mechanisms and functions of mortalin in various biological and pathophysiological contexts, its regulators and effectors, including co-chaperone and clients, as well as the relevance of these aspects in human disease and potential therapeutic strategies. This update is also expected to provide insights into the development of diverse potential therapeutic strategies targeting mortalin.

The Editors invite contributions particularly covering the following areas:

- The role and significance of mortalin in health and disease, including cancer, neurodegeneration, viral infection, and other pathophysiology;
- Canonical vs. non-canonical functions of mortalin in different subcellular locations, e.g., Endoplasmic reticulum-mitochondria tethering, endocytosis, mitochondrial and nuclear proteostasis;
- Signaling pathways and metabolic processes regulated by mortalin;
- Co-chaperones and clients for mortalin;
- Genetic variations of mortalin, including somatic or inherited mutations, and functional consequences;
- Biochemical modifications that regulate mortalin function;
- Drug candidates including small molecule inhibitors.