Involvement of mortalin/GRP75/mthsp70 in the mitochondrial impairments induced by A53T mutant α-synuclein

Liu, Fengtao; Yan, Chen; Yang, Yujie; Yang, Ling; Yu, Mei; Zhao, Jian; Wu, Jianjun; Huang, Fang; Li, Wen; Ding, Zhaofeng; Wang, Jian

doi:10.1016/j.brainres.2015.01.050

Cited by 28 publications

(19 citation statements)

References 34 publications

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“…Mortalin , also known as GRP75 [ 15 ], a member of chaperones and stress related proteins, which plays essential function in mitochondrial proteins folding [ 26 ], cancer cell proliferation, and enhancement of angiogenesis [ 27 ]. In this study, mortalin was found to be down-regulated in the cisplatin-resistant A2780 cisR cell line as compared to the sensitive A2780 cell line, consistent with the earlier studies [ 28 , 29 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

Sequenced Combinations of Cisplatin and Selected Phytochemicals towards Overcoming Drug Resistance in Ovarian Tumour Models

Althurwi

Beale

et al. 2020

IJMS

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In the present study, cisplatin, artemisinin, and oleanolic acid were evaluated alone, and in combination, on human ovarian A2780, A2780ZD0473R, and A2780cisR cancer cell lines, with the aim of overcoming cisplatin resistance and side effects. Cytotoxicity was assessed by MTT reduction assay. Combination index (CI) values were used as a measure of combined drug effect. MALDI TOF/TOF MS/MS and 2-DE gel electrophoresis were used to identify protein biomarkers in ovarian cancer and to evaluate combination effects. Synergism from combinations was dependent on concentration and sequence of administration. Generally, bolus was most synergistic. Moreover, 49 proteins differently expressed by 2 ≥ fold were: CYPA, EIF5A1, Op18, p18, LDHB, P4HB, HSP7C, GRP94, ERp57, mortalin, IMMT, CLIC1, NM23, PSA3,1433Z, and HSP90B were down-regulated, whereas hnRNPA1, hnRNPA2/B1, EF2, GOT1, EF1A1, VIME, BIP, ATP5H, APG2, VINC, KPYM, RAN, PSA7, TPI, PGK1, ACTG and VDAC1 were up-regulated, while TCPA, TCPH, TCPB, PRDX6, EF1G, ATPA, ENOA, PRDX1, MCM7, GBLP, PSAT, Hop, EFTU, PGAM1, SERA and CAH2 were not-expressed in A2780cisR cells. The proteins were found to play critical roles in cell cycle regulation, metabolism, and biosynthetic processes and drug resistance and detoxification. Results indicate that appropriately sequenced combinations of cisplatin with artemisinin (ART) and oleanolic acid (OA) may provide a means to reduce side effects and circumvent platinum resistance.

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Section: Discussionmentioning

confidence: 99%

Sequenced Combinations of Cisplatin and Selected Phytochemicals towards Overcoming Drug Resistance in Ovarian Tumour Models

Althurwi

Beale

et al. 2020

IJMS

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“…Another nuclear-encoded mitochondrial protein, GRP75/mtHSP70 (mortalin), is both imported through the TOM20-TOM22 channel and is reportedly upregulated in response to mitochondrial oxidative stress, which can be caused by α-synuclein toxicity 4,21 . Unlike the imported ETC proteins, mitochondrial expression GRP75 was not significantly affected by αsynuclein overexpression (30% loss; p = 0.5), however, the combined expression of α-synuclein and TOM20 (AAV2-TOM20/αSyn) caused a robust increase in GRP75 (5-fold increase; p < 0.0001) that colocalized with mitochondria in dopaminergic neurons (Figure 5A-B).…”

Section: Mitochondrial Import Of Grp75/mthsp70 Expression Is Stress-rmentioning

confidence: 99%

Protection from α-synuclein-induced dopaminergic neurodegeneration by overexpression of the mitochondrial import receptor TOM20 in the rat midbrain

Miranda

Rocha

Castro

et al. 2020

Preprint

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Dopaminergic neurons of the substantia nigra are selectively vulnerable to mitochondrial dysfunction, which is hypothesized to be an early and fundamental pathogenic mechanism in Parkinson’s disease (PD). Mitochondrial function depends on the successful import of nuclear-encoded proteins, many of which are transported through the TOM20-TOM22 outer mitochondrial membrane import receptor machinery. Recent data suggests that post-translational modifications of α-synuclein promote its interaction with TOM20 at the outer mitochondrial membrane and thereby inhibit normal protein import, which leads to dysfunction and death of dopaminergic neurons. As such, preservation of mitochondrial import in the face of α-synuclein accumulation might be a strategy to prevent dopaminergic neurodegeneration, however, this is difficult to assess using current in vivo models of PD. To this end, we established an exogenous co-expression system, utilizing AAV2 vectors to overexpress human α-synuclein and TOM20, individually or together, in the adult Lewis rat substantia nigra in order to assess whether TOM20 overexpression attenuates α-synuclein-induced dopaminergic neurodegeneration. Twelve weeks after viral injection, we observed that AAV2-TOM20 expression was sufficient to prevent loss of nigral dopaminergic neurons caused by AAV2-αSyn overexpression. The observed TOM20-mediated dopaminergic neuron preservation appeared to be due, in part, to the rescued import of nuclear-encoded mitochondrial electron transport chain proteins that were inhibited by α-synuclein overexpression. In addition, TOM20 overexpression rescued the import of the chaperone protein GRP75/mtHSP70/mortalin, a stress-response protein involved in α-synuclein-induced injury. Collectively, these data indicate that TOM20 expression prevents α-synuclein-induced mitochondrial dysfunction, which is sufficient to rescue dopaminergic neurons in the adult rat brain.

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“…AS binds to the mitochondrial adenine nucleotide translocator (ANT) that is a component of the mitochondrial permeability transition pore , which has been linked to AS cytotoxicity . Furthermore, AS including its oligomeric form binds to the mitochondrial chaperone, mortalin, also known as Heat shock protein A9 that has been implicated in AS cytotoxicity as well .…”

Section: As and Mitochondriamentioning

confidence: 99%

Protein Partners of α‐Synuclein in Health and Disease

Lassen¹,

Reimer²,

Ferreira³

et al. 2016

Brain Pathology

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α-synuclein is normally situated in the nerve terminal but it accumulates and aggregates in axons and cell bodies in synucleinopathies such as Parkinson's disease. The conformational changes occurring during α-synucleins aggregation process affects its interactions with other proteins and its subcellular localization. This review focuses on interaction partners of α-synuclein within different compartments of the cell with a focus on those preferentially binding aggregated α-synuclein. The aggregation state of α-synuclein also affects its catabolism and we hypothesize impaired macroautophagy is involved neuronal excretion of α-synuclein species responsible for the prion-like spreading of α-synuclein pathology.

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Involvement of mortalin/GRP75/mthsp70 in the mitochondrial impairments induced by A53T mutant α-synuclein

Cited by 28 publications

References 34 publications

Sequenced Combinations of Cisplatin and Selected Phytochemicals towards Overcoming Drug Resistance in Ovarian Tumour Models

Sequenced Combinations of Cisplatin and Selected Phytochemicals towards Overcoming Drug Resistance in Ovarian Tumour Models

Protection from α-synuclein-induced dopaminergic neurodegeneration by overexpression of the mitochondrial import receptor TOM20 in the rat midbrain

Protein Partners of α‐Synuclein in Health and Disease

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