Voltage-dependent anion-selective channel (VDAC) interacts with the dynein light chain Tctex1 and the heat-shock protein PBP74

Schwarzer, Christian; Barnikol-Watanabe, Shitsu; Thinnes, Friedrich P.; Hilschmann, Norbert

doi:10.1016/s1357-2725(02)00026-2

Cited by 152 publications

(103 citation statements)

References 40 publications

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“…We were interested in DYNLT1 in our previous works as we tested the existence of an intermediate molecule linking mitochondria and MTs and acting as a protector in regulating mPT under hypoxic condition. Using Y2H assays, we identified DYNLT1 as a promising candidate showing remarkable protein-protein interaction with voltage-dependent anion-selective channel (VDAC, a major porin located on the mitochondrial outer membrane) is in accordance with previous reports (Schwarzer et al, 2002), as well as a co-localization with VDAC1 and MTs (Fang et al, 2011). Therefore we hypothesized that DYNLT1 might be a new modulator of mitochondrial function and MTs stability in hypoxia.…”

Section: Introductionsupporting

confidence: 82%

“…mitochondria) while contributing to their localization (Makokha et al, 2002;Mok et al, 2001;Williams et al, 2005). Schwarzer et al (2002) reported that DYNLT1 slightly increases the voltage-dependence of VDAC1, indicating that DYNLT1 has the ability to modulate channel properties. Our recent findings indicated that DYNYT1 knockdown can negatively affect the mitochondrial permeabilization and metabolism (Fang et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

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Phosphorylation of DYNLT1 at Serine 82 Regulates Microtubule Stability and Mitochondrial Permeabilization in Hypoxia

Xue

Zhang

et al. 2013

Molecules and Cells

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Hypoxia-induced microtubule disruption and mitochondrial permeability transition (mPT) are crucial events leading to fatal cell damage and recent studies showed that microtubules (MTs) are involved in the modulation of mitochondrial function. Dynein light chain Tctex-type 1 (DYNLT1) is thought to be associated with MTs and mitochondria. Previously we demonstrated that DYNLT1 knockdown aggravates hypoxia-induced mitochondrial permeabilization, which indicates a role of DYNLT1 in hypoxic cytoprotection. But the underlying regulatory mechanism of DYNLT1 remains illusive. Here we aimed to investigate the phosphorylation alteration of DYNLT1 at serine 82 (S82) in hypoxia (1% O 2 ). We therefore constructed recombinant adenoviruses to generate S82E and S82A mutants, used to transfect H9c2 and HeLa cell lines. Development of hypoxia-induced mPT (MMP examining, Cyt c release and mPT pore opening assay), hypoxic energy metabolism (cellular viability and ATP quantification), and stability of MTs were examined. Our results showed that phosph-S82 (S82-P) expression was increased in early hypoxia; S82E mutation (phosphomimic) aggravated mitochondrial damage, elevated the free tubulin in cytoplasm and decreased the cellular viability; S82A mutation (dephosphomimic) seemed to diminish the hypoxia-induced injury. These data suggest that DYNLT1 phosphorylation at S82 is involved in MTs and mitochondria regulation, and their interaction and cooperation contribute to the cellular hypoxic tolerance. Thus, we provide new insights into a DYNLT1 mechanism in stabilizing MTs and mitochondria, and propose a potential therapeutic target for hypoxia cytoprotective studies.

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Section: Introductionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Phosphorylation of DYNLT1 at Serine 82 Regulates Microtubule Stability and Mitochondrial Permeabilization in Hypoxia

Xue

Zhang

et al. 2013

Molecules and Cells

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“…Interestingly, Grp78 which normally resides in the ER translocated to the mitochondria and became part of the VDAC-complex after heat shock ( Fig. 4; Schwarzer et al, 2002;He and Lemasters, 2003;Szabadkai and Rizzuto, 2006). Based on these and other findings Szabadkai and Rizzuto (2006) proposed that chaperones might both maintain the communication between the endoplasmic reticulum (ER) and mitochondria as well as protect these organelles from excessive death signals.…”

Section: Chaperones As Key Elements Of Aging Networkmentioning

confidence: 82%

Aging cellular networks: Chaperones as major participants

Sőti

Csermely

2007

Experimental Gerontology

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We increasingly rely on the network approach to understand the complexity of cellular functions. Chaperones (heat shock proteins) are key "networkers", which have among their functions to sequester and repair damaged protein. In order to link the network approach and chaperones with the aging process, we first summarize the properties of aging networks suggesting a "weak link theory of aging". This theory suggests that age-related random damage primarily affects the overwhelming majority of the low affinity, transient interactions (weak links) in cellular networks leading to increased noise, destabilization and diversity. These processes may be further amplified by age-specific network remodelling and by the sequestration of weakly linked cellular proteins to protein aggregates of aging cells. Chaperones are weakly linked hubs [i.e., network elements with a large number of connections] and inter-modular bridge elements of protein-protein interaction, signalling and mitochondrial networks. As aging proceeds, the increased overload of damaged proteins is an especially important element contributing to cellular disintegration and destabilization. Additionally, chaperone overload may contribute to the increase of "noise" in aging cells, which leads to an increased stochastic resonance resulting in a deficient discrimination between signals and noise. Chaperone-and other multi-target therapies, which restore the missing weak links in aging cellular networks, may emerge as important anti-aging interventions.

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“…Hsp75 is an important molecular chaperone in mitochondria, which is a crucial part of the mitochondrial protein import machinery (Krimmer et al, 2000). Studies indicate other mitochondrial proteins, including voltage-dependent anion-selective channel, NADH dehydrogenase, and Hsp60 (Bhattacharyya et al, 1995;Schwarzer et al, 2002) as binding partners of Hsp75, thus suggesting its involvement in multiple mitochondrial functions.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of Mitochondrial Hsp70/Hsp75 Protects Astrocytes against Ischemic Injury in vitro

Voloboueva

Duan

Ouyang

et al. 2007

J Cereb Blood Flow Metab

107

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Mitochondrial heat shock protein 70 (mtHsp70/Hsp75/Grp75/mortalin/TRAP-1/PBP74) is an essential mitochondrial chaperone and a member of the heat shock protein 70 (HSP70) family. Although many studies have shown the protective properties of overexpression of the cytosolic inducible member of the HSP70 family, Hsp72, few studies have investigated the protective potential of Hsp75 against ischemic injury. Mitochondria are one of the primary targets of ischemic injury in astrocytes. In this study, we analyzed the effects of Hsp75 overexpression on cellular levels of reactive oxygen species (ROS), mitochondrial membrane potential, ATP levels, and viability during the ischemia-like conditions of oxygen-glucose deprivation (OGD) or glucose deprivation (GD) in primary astrocytic cultures. We show that Hsp75 overexpression decreases ROS production and preserves mitochondrial membrane potential during GD, and preserves ATP levels and cell viability during OGD. These findings indicate that Hsp75 can provide protection against ischemia-like in vitro injury and suggest that it should be further studied as a potential candidate for protection against ischemic injury.

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Voltage-dependent anion-selective channel (VDAC) interacts with the dynein light chain Tctex1 and the heat-shock protein PBP74

Cited by 152 publications

References 40 publications

Phosphorylation of DYNLT1 at Serine 82 Regulates Microtubule Stability and Mitochondrial Permeabilization in Hypoxia

Phosphorylation of DYNLT1 at Serine 82 Regulates Microtubule Stability and Mitochondrial Permeabilization in Hypoxia

Aging cellular networks: Chaperones as major participants

Overexpression of Mitochondrial Hsp70/Hsp75 Protects Astrocytes against Ischemic Injury in vitro

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