3313

HSPA9

heat shock 70kDa protein 9 (mortalin);HSPA9;heat shock 70kDa protein 9 (mortalin)

75 kDa glucose-regulated protein|catecholamine-regulated protein 40|epididymis secretory sperm binding protein Li 124m|heat shock 70kD protein 9B|mortalin, perinuclear|mortalin-2|p66-mortalin|peptide-binding protein 74|stress-70 protein, mitochondrial

5q31.1

protein-coding

Mortalin (mtHSP70/GRP75) is a heat uninducible member of hsp70 family of proteins. Some of the established features of mortalin include its various subcellular sites, multiple binding partners, and differential subcellular distribution in normal and immortal cells. Overexpression of mortalin leads to extended life span in nematode and normal human cells. On the other hand, it serves as a major target for oxidation and was shown to be involved in old age pathologies including Parkinsons and Alzheimers disease. Since mortalin interacts with many proteins, its modifications in response to stress and damage caused by intracellular oxidation are likely to generate pleiotropic effects. For example, (a) inefficient import of mitochondrial proteins by mortalin-Tim complexes may result into inefficient mitochondrial genesis, energy generation, and functional decline and (b) inefficient chaperoning of proteins can result into a garbage catastrophe.

Although the brain makes up approximately 2% of a persons body weight, it consumes more than 15% of total cardiac output and has a per capita caloric requirement of 10 times more than the rest of the body. Such continuous metabolic demand that supports the generation of action potentials in neuronal cells relies on the mitochondria, the main organelle for power generation. The phenomenon of mitochondrial biogenesis, although has long been a neglected theme in neurobiology, can be regarded as critical to brain physiology. The present review emphasizes the role of a key molecular player of mitochondrial biogenesis, the mortalin/mthsp70. Brain mortalin is discussed in relation to its aptitude to impact on mitochondrial function and homeostasis, to its interfacing energy metabolic functions with synaptic plasticity, and to its modulation of brain aging via the cellular senescence pathways. Recently, this chaperone has been implicated in Alzheimers (AD) and Parkinsons (PD) diseases, with proteomic studies consistently identifying oxidatively-damaged mortalin as potential biomarker. Hence, it is possible that mitochondrial dysfunction coincides with the collapse in the mitochondrial chaperone network that aim not only to import, sort and maintain integrity of protein components within the mitochondria, but also to act as buffer to the molecular heterogeneity of damaged and aging mitochondrial proteins within a ROS-rich microenvironment. Inversely, it may also seem that vulnerability to mitochondrial dysfunction could be precipitated by malevolent (anti-chaperone) gain-of-function of a sick mortalin.

Bcl-2 family of proteins consists of both pro-apoptotic and anti-apoptotic members that control cellular apoptosis. They predominantly reside in the mitochondria and control the release of apoptotic factors from the mitochondria to the cytosol by regulating its membrane potential and opening the PT (permeability transition) pore. Here we report bioinformatics and biochemical evidence to demonstrate the interaction between Bcl-2 and Bcl-xL with a stress chaperone, mortalin. We demonstrate that such interaction results in the abrogation of mortalin-p53 interaction leading to nuclear translocation and transcriptional reactivation of p53 function that results in an induction of senescence in cancer cells.