From proliferative to neurological role of an hsp70 stress chaperone, mortalin
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Although the brain makes up ~2% of a person’s 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 Alzheimer’s (AD) and Parkinson’s (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’.
KeywordsMortalin Chaperone Mitochondrial functions Oxidative stress Neurodegenerative diseases Adult neurogenesis CNS
The postdoctoral fellowship of Custer C. Deocaris is supported by the Japan Society for the Promotion of Science (JSPS).
- Bryant SS, Briggs S, Smithgall TE, Martin GA, McCormick F, Chang JH et al (1995) Two SH2 domains of p120 Ras GTPase-activating protein bind synergistically to tyrosine phosphorylated p190 Rho GTPase-activating protein. J Biol Chem 270:17947–17952. doi: 10.1074/jbc.270.30.17947 PubMedCrossRefGoogle Scholar
- Cajal RY (1928) Degeneration and regeneration of the nervous system (Translated by RM Day from the 1913 Spanish edition) (Oxford University Press)Google Scholar
- Devi L, Prabhu BM, Galati DF, Avadhani NG, Anandatheerthavarada HK (2006) Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer’s disease brain is associated with mitochondrial dysfunction. J Neurosci 26:9057–9068. doi: 10.1523/JNEUROSCI.1469-06.2006 PubMedCrossRefGoogle Scholar
- Geissler A, Rassow J, Pfanner N, Voos W (2001) Mitochondrial import driving forces: enhanced trapping by matrix Hsp70 stimulates translocation and reduces the membrane potential dependence of loosely folded preproteins. Mol Cell Biol 21:7097–7104. doi: 10.1128/MCB.21.20.7097-7104.2001 PubMedCrossRefGoogle Scholar
- Hunzinger C, Wozny W, Schwall GP, Poznanovic S, Stegmann W, Zengerling H et al (2006) Comparative profiling of the mammalian mitochondrial proteome: multiple aconitase-2 isoforms including N-formylkynurenine modifications as part of a protein biomarker signature for reactive oxidative species. J Proteome Res 5:625–633. doi: 10.1021/pr050377+ PubMedCrossRefGoogle Scholar
- Liu Y, Liu W, Song XD, Zuo J (2005) Effect of GRP75/mthsp70/PBP74/mortalin overexpression on intracellular ATP level, mitochondrial membrane potential and ROS accumulation following glucose deprivation in PC12 cells. Mol Cell Biochem 268:45–51. doi: 10.1007/s11010-005-2996-1 PubMedCrossRefGoogle Scholar
- Orsini F, Migliaccio E, Moroni M, Contursi C, Raker VA, Piccini D et al (2004) The life span determinant p66Shc localizes to mitochondria where it associates with mitochondrial heat shock protein 70 and regulates trans-membrane potential. J Biol Chem 279:25689–25695. doi: 10.1074/jbc.M401844200 PubMedCrossRefGoogle Scholar
- Poindexter BJ, Pereira-Smith O, Wadhwa R, Buja LM, Bick RJ (2002) 3D reconstruction and localization of mortalin by deconvolution microscopy. Microsc Anal 89:21–23Google Scholar
- Sanjuan Szklarz LK, Guiard B, Rissler M, Wiedemann N, Kozjak V, van der Laan M et al (2005) Inactivation of the mitochondrial heat shock protein zim17 leads to aggregation of matrix hsp70s followed by pleiotropic effects on morphology and protein biogenesis. J Mol Biol 351:206–218. doi: 10.1016/j.jmb.2005.05.068 PubMedCrossRefGoogle Scholar
- Savel’ev AS, Novikova LA, Kovaleva IE, Luzikov VN, Neupert W, Langer T (1998) ATP-dependent proteolysis in mitochondria. m-AAA protease and PIM1 protease exert overlapping substrate specificities and cooperate with the mtHsp70 system. J Biol Chem 273:20596–20602. doi: 10.1074/jbc.273.32.20596 PubMedCrossRefGoogle Scholar
- Wang C, Thor AD, Moore DH 2nd, Zhao Y, Kerschmann R, Stern R et al (1998) The overexpression of RHAMM, a hyaluronan-binding protein that regulates ras signaling, correlates with overexpression of mitogen-activated protein kinase and is a significant parameter in breast cancer progression. Clin Cancer Res 4:567–576PubMedGoogle Scholar