Dysfunctional Endoplasmic Reticulum-Mitochondrion Coupling Is Associated with Endoplasmic Reticulum Stress-Induced Apoptosis and Neurological Deficits in a Rodent Model of Severe Head Injury

Chen, Xin; Mi, Liang; Gu, Gang; Gao, Xiangyang; Shi, Mingming; Chai, Yan; Chen, Fanglian; Yang, Weidong; Zhang, Jianning

doi:10.1089/neu.2021.0347

Cited by 18 publications

(12 citation statements)

References 67 publications

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“…Recent studies indicated that dysfunctional MAMs might be mainly involved in the neuronal apoptosis and neurological deficits, which is associated with the activation of the PERK pathway. 69 Among the proteins of MAM formation, Mfn2 interacts with PERK to stabilize ER−mitochondrial contacts and involves in mitochondrial fusion and Ca 2+ transport from the ER to mitochondria. Some studies suggested that Mfn2silenced cells showed mitochondrial dysfunction, MAM decrease, and podocyte apoptosis via activating the PERK/ eIF2α/ATF4 pathway.…”

Section: Discussionmentioning

confidence: 99%

“…PERK, as a crucial ER stress sensor of the UPR, is enriched uniquely in the MAMs, which establishes a physical and functional association between the ER and the mitochondria. Recent studies indicated that dysfunctional MAMs might be mainly involved in the neuronal apoptosis and neurological deficits, which is associated with the activation of the PERK pathway . Among the proteins of MAM formation, Mfn2 interacts with PERK to stabilize ER–mitochondrial contacts and involves in mitochondrial fusion and Ca 2+ transport from the ER to mitochondria.…”

Section: Discussionmentioning

confidence: 99%

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Phthalates Induce Neurotoxicity by Disrupting the Mfn2-PERK Axis-Mediated Endoplasmic Reticulum–Mitochondria Interaction

Zhao,

Chang,

Ren

et al. 2024

J. Agric. Food Chem.

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phthalate (DEHP), as the most common phthalate, has been extensively used as a plasticizer to improve the plasticity of agricultural products, which pose severe harm to human health. Mitochondrial dynamics and endoplasmic reticulum (ER) homeostasis are indispensable for maintaining mitochondria-associated ER membrane (MAM) integrity. In this study, we aimed to explore the effect of DEHP on the nervous system and its association with the ER−mitochondria interaction. Here, we showed that DEHP caused morphological changes, motor deficits, cognitive impairments, and blood−brain barrier disruption in the brain. DEHP triggered ER stress, which is mainly mediated by protein kinase R-like endoplasmic reticulum kinase (PERK) signaling. Moreover, DEHP-induced mitofusin-2 (Mfn2) downregulation results in imbalance of the mitochondrial dynamics. Interestingly, DEHP exposure impaired MAMs by inhibiting the Mfn2-PERK interaction. Above all, this study elucidates the disruption of the Mfn2-PERK axis-mediated ER−mitochondria interaction as a phthalate-induced neurotoxicity that could be potentially developed as a novel therapy for neurological diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Phthalates Induce Neurotoxicity by Disrupting the Mfn2-PERK Axis-Mediated Endoplasmic Reticulum–Mitochondria Interaction

Zhao,

Chang,

Ren

et al. 2024

J. Agric. Food Chem.

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“…In particular, we found that, at 5 days post injury, while the mTBI-injured brain activated fusion and inhibited fission, thus promoting mitochondrial recovery, the sTBI-injured brain oppositely activated fission and mitophagy and inhibited fusion, with an overall decrease in the cerebral mitochondrial mass [16]. Therefore, it is conceivable that the profound alterations of MQC following TBI may contribute, through two possible mechanisms, to the depletion of the CoQ pool content occurring in the rat brain tissue following sTBIs only: (i) since sTBI induces sudden and long-lasting alterations in the mitochondrial phosphorylating capacity, causing energy crisis [45,46,53] and dysfunctional mitochondria [16,54], the brain tissue promptly activates the fission and mitophagy processes reducing the number of dysfunctional mitochondria consequently leading to an overall depletion of cerebral CoQ content; (ii) since sTBI induces a downregulation of the genes and protein expressions of mitofusins (MFN1 and MFN2 involved in the regulation of mitochondrial fusion), the decrease in MFN2, a component of the MQC involved in CoQ biosynthesis [29] and the maintenance of correct CoQ levels [55], may certainly contribute to the significant decrease in the CoQ content.…”

Section: Discussionmentioning

confidence: 99%

Traumatic Brain Injury Alters Cerebral Concentrations and Redox States of Coenzymes Q9 and Q10 in the Rat

et al. 2023

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To date, there is no information on the effect of TBI on the changes in brain CoQ levels and possible variations in its redox state. In this study, we induced graded TBIs (mild TBI, mTBI and severe TBI, sTBI) in male rats, using the weight-drop closed-head impact acceleration model of trauma. At 7 days post-injury, CoQ9, CoQ10 and α-tocopherol were measured by HPLC in brain extracts of the injured rats, as well as in those of a group of control sham-operated rats. In the controls, about the 69% of total CoQ was in the form of CoQ9 and the oxidized/reduced ratios of CoQ9 and CoQ10 were, respectively, 1.05 ± 0.07 and 1.42 ± 0.17. No significant changes in these values were observed in rats experiencing mTBI. Conversely, in the brains of sTBI-injured animals, an increase in reduced and a decrease in oxidized CoQ9 produced an oxidized/reduced ratio of 0.81 ± 0.1 (p < 0.001 compared with both controls and mTBI). A concomitant decrease in both reduced and oxidized CoQ10 generated a corresponding oxidized/reduced ratio of 1.38 ± 0.23 (p < 0.001 compared with both controls and mTBI). An overall decrease in the concentration of the total CoQ pool was also found in sTBI-injured rats (p < 0.001 compared with both controls and mTBI). Concerning α-tocopherol, whilst no differences compared with the controls were found in mTBI animals, a significant decrease was observed in rats experiencing sTBI (p < 0.01 compared with both controls and mTBI). Besides suggesting potentially different functions and intracellular distributions of CoQ9 and CoQ10 in rat brain mitochondria, these results demonstrate, for the first time to the best of knowledge, that sTBI alters the levels and redox states of CoQ9 and CoQ10, thus adding a new explanation to the mitochondrial impairment affecting ETC, OXPHOS, energy supply and antioxidant defenses following sTBI.

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“…Another key protein, MFN2, interacts directly with PERK, and the PERK‐MFN2 pair is required for the ER stress‐mediated pathway 119 . PERK also induces Eif2 phosphorylation and the subsequent activation of ATF4, which, in turn, induces an increase in the expression of protein‐folding factor genes, such as CHOP and GRP75, thereby regulating ER homeostasis 94,120 . After ER stress induction, ATF6 response genes are rapidly activated, such as the molecular chaperones (Bip and GRP94) and XBP1 mRNA.…”

Section: Endoplasmic Reticulum Stress and Mammentioning

confidence: 99%

Mitochondria‐associated endoplasmic reticulum membrane: Overview and inextricable link with cancer

Yang

Jing

Song

et al. 2023

J Cellular Molecular Medi

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The mitochondrial‐associated membrane (MAM) is a physical platform that facilitates communication between the endoplasmic reticulum (ER) and mitochondria. It is enriched with many proteins and enzymes and plays an important role in the regulation of several fundamental physiological processes, such as calcium (Ca2+) transfer, lipid synthesis, cellular autophagy and ER stress. Accumulating evidence suggests that oncogenes and suppressor genes are present at the ER‐mitochondrial contact site, and their alterations can affect Ca2+ flux, lipid homeostasis, and the dysregulation of mitochondrial dynamics, thereby influencing the fate of cancer cells. Understanding the fundamental role of MAM‐resident proteins in tumorigenesis could support the search for novel therapeutic targets in cancer. In this review, we summarize the basic structure of MAM and the core functions of MAM‐resident proteins in tumorigenesis. In addition, we discuss the mechanisms by which natural compounds promote cancer cell apoptosis from the perspective of ER stress.

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Dysfunctional Endoplasmic Reticulum-Mitochondrion Coupling Is Associated with Endoplasmic Reticulum Stress-Induced Apoptosis and Neurological Deficits in a Rodent Model of Severe Head Injury

Cited by 18 publications

References 67 publications

Phthalates Induce Neurotoxicity by Disrupting the Mfn2-PERK Axis-Mediated Endoplasmic Reticulum–Mitochondria Interaction

Phthalates Induce Neurotoxicity by Disrupting the Mfn2-PERK Axis-Mediated Endoplasmic Reticulum–Mitochondria Interaction

Traumatic Brain Injury Alters Cerebral Concentrations and Redox States of Coenzymes Q9 and Q10 in the Rat

Mitochondria‐associated endoplasmic reticulum membrane: Overview and inextricable link with cancer

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