The Putative Helical Lid of the Hsp70 Peptide-binding Domain is Required for Efficient Preprotein Translocation into Mitochondria

Strub, Andreas; Zufall, Nicole; Voos, Wolfgang

doi:10.1016/j.jmb.2003.10.023

Cited by 19 publications

(8 citation statements)

References 52 publications

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“…Alternatively, this region may be required by ZnT2 to form intermolecular complexes that target ZnT2 to the mitochondrial membrane. For example, heat shock protein (Hsp)70 is a ubiquitous protein that performs critical functions such as binding to unfolded segments of protein substrates to assist in protein folding, cellular transport, and translocation across intracellular membranes (36). Analysis of the yeast homolog mtHsp70 (Ssc1) implicates its essentiality in the translocation of cytosolic proteins across both mitochondrial membranes (37).…”

Section: Discussionmentioning

confidence: 99%

A histidine-rich motif mediates mitochondrial localization of ZnT2 to modulate mitochondrial function

Seo

López

Kelleher³

2011

American Journal of Physiology-Cell Physiology

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Female reproductive tissues such as mammary glands, ovaries, uterus, and placenta are phenotypically dynamic, requiring tight integration of bioenergetic and apoptotic mechanisms. Mitochondrial zinc (Zn) pools have emerged as a central player in regulating bioenergetics and apoptosis. Zn must first be imported into mitochondria to modulate mitochondrion-specific functions; however, mitochondrial Zn import mechanisms have not been identified. Here we documented that the Zn transporter ZnT2 is associated with the inner mitochondrial membrane and acts as an auxiliary Zn importer into mitochondria in mammary cells. We found that attenuation of ZnT2 expression significantly reduced mitochondrial Zn uptake and total mitochondrial Zn pools. Moreover, expression of a ZnT2-hemagglutinin (HA) fusion protein was localized to mitochondria and significantly increased Zn uptake and mitochondrial Zn pools, directly implicating ZnT2 in Zn import into mitochondria. Confocal microscopy of truncated and point mutants of ZnT2-green fluorescent protein (GFP) fusion proteins revealed a histidine-rich motif ((51)HHXH(54)) in the NH(2) terminus that is important for mitochondrial targeting of ZnT2. More importantly, the expansion of mitochondrial Zn pools by ZnT2 overexpression significantly reduced ATP biogenesis and mitochondrial oxidation concurrent with increased apoptosis, suggesting a functional role for ZnT2-mediated Zn import into mitochondria. These results identify the first Zn transporter directly associated with mitochondria and suggest that unique secretory tissues such as the mammary gland require novel mechanisms to modulate mitochondrion-specific functions.

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Section: Discussionmentioning

confidence: 99%

A histidine-rich motif mediates mitochondrial localization of ZnT2 to modulate mitochondrial function

Seo

López

Kelleher³

2011

American Journal of Physiology-Cell Physiology

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“…Overexpression of mortalin (HSP70) leads to lifespan extension suggesting that the decline in mortalin level and thus, its function(s) determine fixed proliferation potential of normal cells and ageing. In corollary, deletion mutations of SSC1, the yeast orthologue of mthsp70, were lethal (Craig et al 1989;Davis et al 1999;Strub et al 2003) and knockdown of mortalin with ribozyme or antisense inevitably led to cellular growth arrest (Wadhwa et al 2003;. Worms treated with siRNA against Hsp-6 (hsp70F), a nematode orthologue of mortalin, caused a reduction in the level of ATP-2, Hsp60 and CLK-1, leading to abnormal mitochondrial morphology, lower ATP production and accelerated ageing or progeria-like phenotypes (Kimura et al 2007).…”

Section: Mitochondrial Dysfunctions In Ageingmentioning

confidence: 99%

Mitochondrial dysfunction in some oxidative stress-related genetic diseases: Ataxia-Telangiectasia, Down Syndrome, Fanconi Anaemia and Werner Syndrome

et al. 2010

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Oxidative stress is a phenotypic hallmark in several genetic disorders characterized by cancer predisposition and/or propensity to premature ageing. Here we review the published evidence for the involvement of oxidative stress in the phenotypes of Ataxia-Telangiectasia (A-T), Down Syndrome (DS), Fanconi Anaemia (FA), and Werner Syndrome (WS), from the viewpoint of mitochondrial dysfunction. Mitochondria are recognized as both the cell compartment where energetic metabolism occurs and as the first and most susceptible target of reactive oxygen species (ROS) formation. Thus, a critical evaluation of the basic mechanisms leading to an in vivo pro-oxidant state relies on elucidating the features of mitochondrial impairment in each disorder. The evidence for different mitochondrial dysfunctions reported in A-T, DS, and FA is reviewed. In the case of WS, clear-cut evidence linking human WS phenotype to mitochondrial abnormalities is lacking so far in the literature. Nevertheless, evidence relating mitochondrial dysfunctions to normal ageing suggests that WS, as a progeroid syndrome, is likely to feature mitochondrial abnormalities. Hence, ad hoc research focused on elucidating the nature of mitochondrial dysfunction in WS pathogenesis is required. Based on the recognized, or reasonably suspected, role of mitochondrial abnormalities in the pathogenesis of these disorders, studies of chemoprevention with mitochondria-targeted supplements are warranted.

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“…While tethered onto the inner face of the inner mitochondrial membrane, Tim44 is transiently associated with mortalin/mtHsp70, the 2 cochaperone J-proteins, Pam18 and Pam16 (a degenerate J-protein), and the nucleotide exchange factor Mge1 (homolog of the bacterial GrpE), to form an ATP-driven import complex, called the presequence translocase-associated motor (PAM) (D 'Silva et al 2004). The binding sites of Mge1 and Tim44 to mortalin have been assigned at the variable region along C-terminal ␣-helical lid (Strub et al 2003). During the translocation, Mge1 enhances the otherwise low intrinsic ATPase activity of mortalin via the release of ADP and Pi (Dekker and Pfanner 1997).…”

Section: Mortalin In Preprotein Translocationmentioning

confidence: 99%

On the brotherhood of the mitochondrial chaperones mortalin and heat shock protein 60

2006

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The heat shock chaperones mortalin/mitochondrial heat shock protein 70 (mtHsp70) and Hsp60 are found in multiple subcellular sites and function in the folding and intracellular trafficking of many proteins. The chaperoning activity of these 2 proteins involves different structural and functional mechanisms. In spite of providing an excellent model for an evolutionarily conserved molecular ''brotherhood,'' their individual functions, although overlapping, are nonredundant. As they travel to various locations, both chaperones acquire different binding partners and exert a more divergent involvement in tumorigenesis, cellular senescence, and immunology. An understanding of their functional biology may lead to novel designing and development of therapeutic strategies for cancer and aging.

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The Putative Helical Lid of the Hsp70 Peptide-binding Domain is Required for Efficient Preprotein Translocation into Mitochondria

Cited by 19 publications

References 52 publications

A histidine-rich motif mediates mitochondrial localization of ZnT2 to modulate mitochondrial function

A histidine-rich motif mediates mitochondrial localization of ZnT2 to modulate mitochondrial function

Mitochondrial dysfunction in some oxidative stress-related genetic diseases: Ataxia-Telangiectasia, Down Syndrome, Fanconi Anaemia and Werner Syndrome

On the brotherhood of the mitochondrial chaperones mortalin and heat shock protein 60

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