The MKK7 inhibitor peptide GADD45β-I attenuates ER stress-induced mitochondrial dysfunction in HT22 cells: Involvement of JNK-Wnt pathway

Xu, Quanhua; Song, Bing-Jun; Liu, Dan; Chen, Yuhua; Zhou, Yuan; Liu, Wenbo; Li, Hua; Long, Tianlin; Zhang, Rui; Liu, Wei

doi:10.1016/j.brainres.2018.04.012

Cited by 6 publications

(3 citation statements)

References 42 publications

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“…Subsequent disruption of inter-organelle communication has been previously shown to induce ER stress [77]. Conversely, ER stress can induce mitochondrial dysfunction [96]. Increased ER stress has been observed in iPSC-derived motor neurons from C9-HRE-carrying ALS/FTLD patients [85].…”

Section: Discussionmentioning

confidence: 99%

FTLD Patient–Derived Fibroblasts Show Defective Mitochondrial Function and Accumulation of p62

et al. 2021

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Frontotemporal lobar degeneration (FTLD) is a clinically, genetically, and neuropathologically heterogeneous group of neurodegenerative syndromes, leading to progressive cognitive dysfunction and frontal and temporal atrophy. C9orf72 hexanucleotide repeat expansion (C9-HRE) is the most common genetic cause of FTLD, but pathogenic mechanisms underlying FTLD are not fully understood. Here, we compared cellular features and functional properties, especially related to protein degradation pathways and mitochondrial function, of FTLD patient–derived skin fibroblasts from C9-HRE carriers and non-carriers and healthy donors. Fibroblasts from C9-HRE carriers were found to produce RNA foci, but no dipeptide repeat proteins, and they showed unchanged levels of C9orf72 mRNA transcripts. The main protein degradation pathways, the ubiquitin–proteasome system and autophagy, did not show alterations between the fibroblasts from C9-HRE-carrying and non-carrying FTLD patients and compared to healthy controls. An increase in the number and size of p62-positive puncta was evident in fibroblasts from both C9-HRE carriers and non-carriers. In addition, several parameters of mitochondrial function, namely, basal and maximal respiration and respiration linked to ATP production, were significantly reduced in the FTLD patient–derived fibroblasts from both C9-HRE carriers and non-carriers. Our findings suggest that FTLD patient–derived fibroblasts, regardless of whether they carry the C9-HRE expansion, show unchanged proteasomal and autophagic function, but significantly impaired mitochondrial function and increased accumulation of p62 when compared to control fibroblasts. These findings suggest the possibility of utilizing FTLD patient–derived fibroblasts as a platform for biomarker discovery and testing of drugs targeted to specific cellular functions, such as mitochondrial respiration.

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Section: Discussionmentioning

confidence: 99%

FTLD Patient–Derived Fibroblasts Show Defective Mitochondrial Function and Accumulation of p62

et al. 2021

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“…The accumulation of DNA damage and damaged DNA repair ability are the important mechanisms that make it difficult to recover nerve function after cerebral I/R. As a stress response gene, Gadd45β affects cell apoptosis, growth and DNA repair [17,18]. DNA-PKcs, as a catalytic subunit of DNA-dependent proteases, are mainly engaged in double-stranded DNA fracture repair and serve as the center of DNA repair in non-proliferating cells, limiting the accumulation of DNA damage [19].…”

Section: Discussionmentioning

confidence: 99%

Effect of Different Exercise Intensity Preconditioning on Global Ischemia-Induced Neuronal Death and Expression of Gadd45β and DNA-PKcs in Rats

Sun¹,

Zhao²,

Li³

et al. 2020

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“…ER and mitochondria both have dynamic plasticity of their structure in response to cellular requirements, which is the prerequisite for ER-mitochondrial communication functionally and structurally (Bravo-Sagua et al, 2013). The activation of ER stress induced the mitochondrial dysfunction in HT22 cells (Xu et al, 2018), and ER stress sensitized the mitochondria by opening its permeability transition pore in cardiac injury (Chen et al, 2017). Consistent with these studies, our results demonstrate that in cortical neurons under I/R injury, the reactivation of Homer1a overexpression suppressed ER stress via TM, which led to increased intracellular calcium load, elevated ROS production and ATP loss.…”

Section: Discussionmentioning

confidence: 99%

Homer1a Attenuates Endoplasmic Reticulum Stress-Induced Mitochondrial Stress After Ischemic Reperfusion Injury by Inhibiting the PERK Pathway

Wei

Luo

et al. 2019

Front. Cell. Neurosci.

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Homer1a is the short form of a scaffold protein that plays a protective role in many forms of stress. However, the role of Homer1a in cerebral ischemia/reperfusion (I/R) injury and its potential mechanism is still unknown. In this study, we found that Homer1a was upregulated by oxygen and glucose deprivation (OGD) and that overexpression of Homer1a alleviated OGD-induced lactate dehydrogenase (LDH) release and cell death in cultured cortical neurons. After OGD treatment, the overexpression of Homer1a preserved mitochondrial function, as evidenced by less cytochrome c release, less reactive oxygen species (ROS) production, less ATP and mitochondrial membrane potential (MMP) loss, less caspase-9 activation, and inhibition of endoplasmic reticulum (ER) stress confirmed by the decreased expression of phosphate-PKR-like ER Kinase (p-PERK)/PERK and phosphate- inositol-requiring enzyme 1 (p-IRE1)/IRE1 and immunofluorescence (IF) staining. In addition, mitochondrial protection of Homer1a was blocked by the ER stress activator Tunicamycin (TM) with a re-escalated ROS level, increasing ATP and MMP loss. Furthermore, Homer1a overexpression-induced mitochondrial stress attenuation was significantly reversed by activating the PERK pathway with TM and p-IRE1 inhibitor 3,5-dibromosalicylaldehyde (DBSA), as evidenced by increased cytochrome c release, increased ATP loss and a higher ROS level. However, activating the IRE1 pathway with TM and p-PERK inhibitor GSK2656157 showed little change in cytochrome c release and exhibited a moderate upgrade of ATP loss and ROS production in neurons. In summary, these findings demonstrated that Homer1a protects against OGD-induced injury by preserving mitochondrial function through inhibiting the PERK pathway. Our finding may reveal a promising target of protecting neurons from cerebral I/R injury.

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The MKK7 inhibitor peptide GADD45β-I attenuates ER stress-induced mitochondrial dysfunction in HT22 cells: Involvement of JNK-Wnt pathway

Cited by 6 publications

References 42 publications

FTLD Patient–Derived Fibroblasts Show Defective Mitochondrial Function and Accumulation of p62

FTLD Patient–Derived Fibroblasts Show Defective Mitochondrial Function and Accumulation of p62

Effect of Different Exercise Intensity Preconditioning on Global Ischemia-Induced Neuronal Death and Expression of Gadd45β and DNA-PKcs in Rats

Homer1a Attenuates Endoplasmic Reticulum Stress-Induced Mitochondrial Stress After Ischemic Reperfusion Injury by Inhibiting the PERK Pathway

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