Reduction of ER-Mitochondria Distance: a Key Feature in Alzheimer’s and Parkinson’s Disease, and During Cancer Treatment

Perez-Leanos, Carmen A.; Romero-Campos, Hugo E.; Dupont, Geneviève; González‐Vélez, Virginia

doi:10.1109/embc46164.2021.9631090

Cited by 11 publications

(9 citation statements)

References 17 publications

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“…MAM dysfunction is associated with various neurodegenerative diseases (Manganelli et al, 2020;Yuan et al, 2020). The distance between the mitochondria and endoplasmic reticulum (ER) is important for maintaining MAM homeostasis; a significant reduction in this distance has been observed in central nervous system degeneration, including Alzheimer's disease and Parkinson's disease (Perez-Leanos et al, 2021). However, alterations in MAMs in retinal cells under ocular hypertension-associated oxidative damage and how MAM dysregulation leads to retinal cell death have not been studied.…”

Section: Introductionmentioning

confidence: 99%

Olaparib, a PARP-1 inhibitor, protects retinal cells from ocular hypertension-associated oxidative damage

Yang

Lü

et al. 2022

Front. Cell Dev. Biol.

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Glaucoma is the most common cause of irreversible blindness worldwide. Elevated intraocular pressure (IOP) and relative hypoxia in the retina stimulate the production of reactive oxygen species (ROS), which, in turn, puts the retina and optic nerve under chronic oxidative stress. Emerging evidence has shown that oxidative stress can trigger PARP-1 overactivation, mitochondrial-associated endoplasmic reticulum membrane (MAM) dysregulation, and NLRP3 activation. Oxidative damage can trigger inflammasome activation, and NLRP3 is the only inflammasome associated with MAM dysregulation. In addition, multiple transcription factors are located on the MAM. This study aimed to investigate the protective effects and underlying mechanisms of a PARP-1 inhibitor (olaparib) against chronic ocular hypertension-associated retinal cell damage. We also mimicked hypoxic stimulation of a retinal precursor cell line by exposing the cells to 0.2% O2in vitro. We discovered that chronic ocular hypertension (COH) induces oxidative damage and MAM dysregulation in the retinal ganglion cells (RGCs). The protein levels of cleaved-PARP and NLRP3 were upregulated in the retinas of the COH rats. Olaparib, a PARP-1 inhibitor, alleviated COH-induced RGC loss, retinal morphological alterations, and photopic negative response amplitude reduction. Olaparib also relieved hypoxic stimulation-induced loss of cell viability and MAM dysregulation. Additionally, some indicators of mitochondrial performance, such as reactive oxygen species accumulation, mitochondrial Ca2+ influx, and mitochondrial membrane potential collapse, decreased after olaparib treatment. Olaparib attenuated the hypoxia-induced upregulation of NLRP3 protein levels as well as the phosphorylation of ERK1/2 and histone H2A.X. These results suggest that olaparib protects RGCs from chronic intraocular pressure elevation in vivo and alleviates the abnormal MAM dysregulation and mitochondrial dysfunction caused by hypoxia in vitro. This protection may be achieved by inhibiting PARP-1 overactivation, NLRP3 upregulation, and phosphorylation of ERK1/2.

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Section: Introductionmentioning

confidence: 99%

Olaparib, a PARP-1 inhibitor, protects retinal cells from ocular hypertension-associated oxidative damage

Yang

Lü

et al. 2022

Front. Cell Dev. Biol.

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“…The MAM is a special membrane that mediates ER–mitochondrion communication and participates in protein and metabolite exchange . The distance of the MAM (either too close or too far) affects its function. , In the control group, most mitochondria and the ER showed a normal morphology and a clear structure (Figure A,B). In the 4-PBA group, the ER and mitochondrial morphologies, and the distance between the ER and mitochondrial membranes, were similar to those in the control group.…”

Section: Resultsmentioning

confidence: 98%

“…The MAM is a communication platform between the mitochondria and ER, which maintains cell function and survival by precisely regulating the calcium ion exchange between the two organelles. , The function of the MAM can be affected by the distance between ER and mitochondria (too close or too far). , However, until now, we lacked data on the effects of 7S/11S on IPEC-J2 cells MAM. The mitochondria–ER colocalization and MAM ultrastructure showed that 7S/11S increased the distance of MAM and significantly decreased the Pearson coefficient of mitochondria–ER colocalization, which was reversed after 4-PBA treatment.…”

Section: Discussionmentioning

confidence: 99%

4-Phenylbutyric Acid Attenuates Soybean Glycinin/β-Conglycinin-Induced IPEC-J2 Cells Apoptosis by Regulating the Mitochondria-Associated Endoplasmic Reticulum Membrane and NLRP-3

Wang,

Zhang,

Jiang

et al. 2024

J. Agric. Food Chem.

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Glycinin (11S) and β-conglycinin (7S) from soybean (glycine max) cause diarrhea and intestinal barrier damage in young animals. Understanding the mechanisms underlying the damage caused by 7S and 11S, it is vital to develop strategies to eliminate allergenicity. Consequently, we investigated 7S/11S-mediated apoptosis in porcine intestinal epithelial (IPEC-J2) cells. IPEC-J2 cells suffered endoplasmic reticulum stress (ERS) in response to 7S and 11S, activating protein kinase RNA-like ER kinase, activating transcription factor 6, C/EBP homologous protein, and inositol-requiring enzyme 1 alpha. 4-Phenylbutyric acid (4-PBA) treatment alleviated ERS; reduced the NLR family pyrin domain containing 3, interleukin-1β, and interleukin-18 levels; inhibited apoptosis; increased mitofusin 2 expression; and mitigated Ca 2+ overload and mitochondria-associated ER membrane (MAM) dysfunction, thereby ameliorating IPEC-J2 injury. We demonstrated the pivotal role of ERS in MAM dysfunction and 7S-and 11Smediated apoptosis, providing insights into 7S-and 11S-mediated intestinal barrier injury prevention and treatment.

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“…This connection may be related to the communication between ER and mitochondria. Recent studies have shown that mitochondria form close physical contacts with a specialized domain of the ER, known as the mitochondria-associated membrane (MAM) [ 43 ], and this association constitutes a key signaling hub to regulate a plethora of fundamental cellular processes, such as Ca 2+ homeostasis, lipid synthesis and mitophagy [ 43 , 44 , 45 ]. Intriguingly, many of these cellular processes are perturbed in neurodegenerative diseases and increasing evidence highlights that alterations in ER-mitochondria signaling contribute to these diseases, including PD.…”

Section: Discussionmentioning

confidence: 99%

The Degradation of TMEM166 by Autophagy Promotes AMPK Activation to Protect SH-SY5Y Cells Exposed to MPP+

Liao

Gong

Wang

et al. 2022

Cells

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Neuronal oxidative stress caused by mitochondrial dysfunction plays a crucial role in the development of Parkinson’s disease (PD). Growing evidence shows that autophagy confers neuroprotection in oxidative-stress-associated PD. This work aims to investigate the involvement of TMEM166, an endoplasmic-reticulum-localized autophagy-regulating protein, in the process of PD-associated oxidative stress through the classic cellular PD model of neuroblastoma SH-SY5Y cells exposed to 1-methyl-4-phenylpyridinium (MPP+). Reactive oxygen species (ROS) production and mitochondrial membrane potential were checked to assess the oxidative stress induced by MPP+ and the cellular ATP generated was determined to evaluate mitochondrial function. The effect on autophagy induction was evaluated by analyzing p62 and LC3-II/I expression and by observing the LC3 puncta and the colocalization of LC3 with LAMP1/ LAMP2. The colocalization of mitochondria with LC3, the colocalization of Tom20 with LAMP1 and Tom20 expression were analyzed to evaluate mitophagy. We found that TMEM166 is up-regulated in transcript levels, but up-regulated first and then down-regulated by autophagic degradation in protein levels upon MPP+-treatment. Overexpression of TMEM166 induces mitochondria fragmentation and dysfunction and exacerbates MPP+-induced oxidative stress and cell viability reduction. Overexpression of TMEM166 is sufficient to induce autophagy and mitophagy and promotes autophagy and mitophagy under MPP+ treatment, while knockdown of TMEM166 inhibits basal autophagic degradation. In addition, overexpressed TMEM166 suppresses AMPK activation, while TMEM166 knockdown enhances AMPK activation. Pharmacological activation of AMPK alleviates the exacerbation of oxidative stress induced by TMEM166 overexpression and increases cell viability, while pharmacological inhibition mitophagy aggravates the oxidative stress induced by MPP+ treatment combined with TMEM166 overexpression. Finally, we find that overexpressed TMEM166 partially localizes to mitochondria and, simultaneously, the active AMPK in mitochondria is decreased. Collectively, these findings suggest that TMEM166 can translocate from ER to mitochondria and inhibit AMPK activation and, in response to mitochondrial oxidative stress, neuronal cells choose to up-regulate TMEM166 to promote autophagy/mitophagy; then, the enhancing autophagy/mitophagy degrades the TMEM166 to activate AMPK, by the two means to maintain cell survival. The continuous synthesis and degradation of TMEM166 in autophagy/mitochondria flux suggest that TMEM166 may act as an autophagy/mitochondria adaptor.

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Reduction of ER-Mitochondria Distance: a Key Feature in Alzheimer’s and Parkinson’s Disease, and During Cancer Treatment

Cited by 11 publications

References 17 publications

Olaparib, a PARP-1 inhibitor, protects retinal cells from ocular hypertension-associated oxidative damage

Olaparib, a PARP-1 inhibitor, protects retinal cells from ocular hypertension-associated oxidative damage

4-Phenylbutyric Acid Attenuates Soybean Glycinin/β-Conglycinin-Induced IPEC-J2 Cells Apoptosis by Regulating the Mitochondria-Associated Endoplasmic Reticulum Membrane and NLRP-3

The Degradation of TMEM166 by Autophagy Promotes AMPK Activation to Protect SH-SY5Y Cells Exposed to MPP+

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