A trio has turned into a quartet: DJ-1 interacts with the IP3R-Grp75-VDAC complex to control ER-mitochondria interaction

Basso, Valentina; Marchesan, Elena; Ziviani, Elena

doi:10.1016/j.ceca.2020.102186

Cited by 35 publications

(34 citation statements)

References 10 publications

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“…As described previously, the PDrelated protein DJ-1 has been shown to interact with VDAC, GRP75 and IP 3 R in a tetramer complex, and is thought to facilitate Ca 2+ homoeostasis, as well as acting as a functional tether. Ablation of DJ-1 decreases MERCS association and alters Ca 2+ handling, which can be rescued with WT but not PD-related mutant DJ-1 [5,6]. Furthermore, both PINK1 and Parkin, two genes mutated in autosomal recessive PD, acting together to regulate MQC mechanisms, have been found to localise to MERCS under mitophagy induction [70].…”

Section: Parkinson's Diseasementioning

confidence: 99%

“…Together, IP 3 R, VDAC, GRP75 and DJ-1 act as a tetramer complex to regulate the transfer of Ca 2+ from the ER to the mitochondrial matrix via the mitochondrial calcium uniporter (MCU). Interestingly, complete loss of IP 3 R did not show a physical alteration in MERCS; however, the loss of GRP75 or DJ-1 abolishes the Ca 2+ influx into the mitochondria [5][6][7] suggesting that the tetramer of VDAC, Fig. 1 The molecular composition of mitochondria-ER contact sites: several sets of complexes tether the mitochondria and ER.…”

Section: Ip3r-dj-1-grp75-vdacmentioning

confidence: 99%

“…The first tethering complex identified was between the voltage-dependent anion channel (VDAC) (an outer mitochondrial membrane (OMM) protein) and the ERresiding inositol 1,4,5-triphosphate receptor (IP 3 R). This interaction is regulated by glucose-related protein 75 (GRP75) (a molecular chaperone) and deglycase (DJ-1), a protein mutated in PD, that has been revealed to interact with VDAC, IP 3 R and GRP75 [5,6]. Together, IP 3 R, VDAC, GRP75 and DJ-1 act as a tetramer complex to regulate the transfer of Ca 2+ from the ER to the mitochondrial matrix via the mitochondrial calcium uniporter (MCU).…”

Section: Ip3r-dj-1-grp75-vdacmentioning

confidence: 99%

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ER-mitochondria contact sites in neurodegeneration: genetic screening approaches to investigate novel disease mechanisms

Wilson

Metzakopian

2020

Cell Death Differ

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Mitochondria-ER contact sites (MERCS) are known to underpin many important cellular homoeostatic functions, including mitochondrial quality control, lipid metabolism, calcium homoeostasis, the unfolded protein response and ER stress. These functions are known to be dysregulated in neurodegenerative diseases, including Parkinson’s disease (PD), Alzheimer’s disease (AD) and amyloid lateral sclerosis (ALS), and the number of disease-related proteins and genes being associated with MERCS is increasing. However, many details regarding MERCS and their role in neurodegenerative diseases remain unknown. In this review, we aim to summarise the current knowledge regarding the structure and function of MERCS, and to update the field on current research in PD, AD and ALS. Furthermore, we will evaluate high-throughput screening techniques, including RNAi vs CRISPR/Cas9, pooled vs arrayed formats and how these could be combined with current techniques to visualise MERCS. We will consider the advantages and disadvantages of each technique and how it can be utilised to uncover novel protein pathways involved in MERCS dysfunction in neurodegenerative diseases.

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Section: Parkinson's Diseasementioning

confidence: 99%

Section: Ip3r-dj-1-grp75-vdacmentioning

confidence: 99%

Section: Ip3r-dj-1-grp75-vdacmentioning

confidence: 99%

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ER-mitochondria contact sites in neurodegeneration: genetic screening approaches to investigate novel disease mechanisms

Wilson

Metzakopian

2020

Cell Death Differ

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“…This is further corroborated by our finding of elevated levels of GRP75 with acute rotenone, but dramatic loss of GRP75 with chronic rotenone exposure, at a time when mitochondrial import is known to be impaired 1 . As a multifunctional, redox sensitive protein, reduced GRP75 expression in dopaminergic neurons from α-synuclein overexpression or rotenone exposure may contribute to several pro-death pathways, including calcium dysregulation 32 , energy depravation 33 , and apoptotic signaling 34 .…”

Section: Discussionmentioning

confidence: 99%

Protection from α-Synuclein induced dopaminergic neurodegeneration by overexpression of the mitochondrial import receptor TOM20

Miranda

Rocha

Castro

et al. 2020

npj Parkinsons Dis.

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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, leading 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 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 expression (and presumed import) of nuclear-encoded mitochondrial electron transport chain proteins that were inhibited by α-synuclein overexpression. In addition, TOM20 overexpression rescued the expression 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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“…Forms complexes with IP3Rs [103] Infertility [104] DJ-1 Interacts with the IP3R [105] Related with AS [106] and polymorphisms associated with infertility [107]…”

Section: Pc2mentioning

confidence: 99%

IP3R Channels in Male Reproduction

Zhang

Huang

Zhou

et al. 2020

IJMS

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As a second messenger in cellular signal transduction, calcium signaling extensively participates in various physiological activities, including spermatogenesis and the regulation of sperm function. Abnormal calcium signaling is highly correlated with male infertility. Calcium signaling is mainly regulated by both extracellular calcium influx and the release of calcium stores. Inositol 1,4,5-trisphosphate receptor (IP3R) is a widely expressed channel for calcium stores. After being activated by inositol 1,4,5-trisphosphate (IP3) and calcium signaling at a lower concentration, IP3R can regulate the release of Ca2+ from stores into cytoplasm, and eventually trigger downstream events. The closure of the IP3R channel caused by a rise in intracellular calcium signals and the activation of the calcium pump jointly restores the calcium store to a normal level. In this review, we aim to discuss structural features of IP3R channels and the underlying mechanism of IP3R channel-mediated calcium signaling and further focus on the research progress of IP3R expression and function in the male reproductive system. Finally, we propose key directions and strategies for research of IP3R in spermatogenesis and the regulation of sperm function to provide more understanding of the function and mechanism of IP3R channel actions in male reproduction.

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A trio has turned into a quartet: DJ-1 interacts with the IP3R-Grp75-VDAC complex to control ER-mitochondria interaction

Cited by 35 publications

References 10 publications

ER-mitochondria contact sites in neurodegeneration: genetic screening approaches to investigate novel disease mechanisms

ER-mitochondria contact sites in neurodegeneration: genetic screening approaches to investigate novel disease mechanisms

Protection from α-Synuclein induced dopaminergic neurodegeneration by overexpression of the mitochondrial import receptor TOM20

IP3R Channels in Male Reproduction

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