Atf-6 Regulates Lifespan through ER-Mitochondrial Calcium Homeostasis

Burkewitz, Kristopher; Feng, Gaomin; Dutta, Sneha; Kelley, Charlotte A.; Steinbaugh, Michael J.; Cram, Erin J.; Mair, William

doi:10.1016/j.celrep.2020.108125

Cited by 52 publications

(50 citation statements)

References 46 publications

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“…Loss of ire-1 or pek-1 was known to affect various basal physiology, such as secretory-protein metabolism, longevity, or development 43 - 45 ; therefore, the basal chemotaxis indices of ire-1 and pek-1 mutants seemed to decrease in the control group compared to that of N2. Unlike ire-1 or pek-1 , the atf-6 mutants were known to have extended lifespan without sensitivity to proteotoxic stress 46 , 47 , and the results of chemotaxis index were not different from that of N2. The other two mutants, sel-1 and sel-11 , also showed different chemotaxis indices from those of N2.…”

Section: Discussionmentioning

confidence: 92%

Role of Unfolded Protein Response and Endoplasmic Reticulum-Associated Degradation by Repeated Exposure to Inhalation Anesthetics in Caenorhabditis elegans

Kim¹,

Shin²,

Hwan³

et al. 2021

Int. J. Med. Sci.

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Background: When an imbalance occurs between the demand and capacity for protein folding, unfolded proteins accumulate in the endoplasmic reticulum (ER) lumen and activate the unfolded protein response (UPR). In addition, unfolded proteins are cleared from the ER lumen for ubiquitination and subsequent cytosolic proteasomal degradation, which is termed as the ER-associated degradation (ERAD) pathway. This study focused on changes in the UPR and ERAD pathways induced by the repeated inhalation anesthetic exposure in Caenorhabditis elegans . Methods : Depending on repeated isoflurane exposure, C. elegans was classified into the control or isoflurane group. To evaluate the expression of a specific gene, RNA was extracted from adult worms in each group and real-time polymerase chain reaction was performed. Ubiquitinated protein levels were measured using western blotting, and behavioral changes were evaluated by chemotaxis assay using various mutant strains. Results : Isoflurane upregulated the expression of ire-1 and pek-1 whereas the expression of atf-6 was unaffected. The expression of both sel-1 and sel-11 was decreased by isoflurane exposure, possibly indicating the inhibition of retro-translocation. The expression of cdc-48.1 and cdc-48.2 was decreased and higher ubiquitinated protein levels were observed in the isoflurane group than in the control, suggesting that deubiquitination and degradation of misfolded proteins were interrupted. The chemotaxis indices of ire-1 , pek-1 , sel-1 , and sel-11 mutants decreased significantly compared to N2, and they were not suppressed further even after the repeated isoflurane exposure. Conclusion : Repeated isoflurane exposure caused significant ER stress in C. elegans . Following the increase in UPR, the ERAD pathway was disrupted by repeated isoflurane exposure and ubiquitinated proteins was accumulated subsequently. UPR and ERAD pathways are potential modifiable neuroprotection targets against anesthesia-induced neurotoxicity.

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Section: Discussionmentioning

confidence: 92%

Role of Unfolded Protein Response and Endoplasmic Reticulum-Associated Degradation by Repeated Exposure to Inhalation Anesthetics in Caenorhabditis elegans

Kim¹,

Shin²,

Hwan³

et al. 2021

Int. J. Med. Sci.

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“…Recently Burkewitz et al 2020 demonstrated the loss of atf6 promotes longevity in C elegans. Interestingly, the life span extension is not through canonical proteostasis pathways but through the modulation of ER-mitochondrial calcium homeostasis.…”

Section: Atf6mentioning

confidence: 99%

“…Atf-6 regulates the ER function and lifespan through its proximal mediator, calreticulin/crt-1. As a downstream effect, the ER calcium release further leads to changes in mitochondrial dynamics and bioenergetics [169]. Not only in C elegans, another study conducted by Wang et al 2018 with human mesenchymal stem cells (hMSCs) also showed that ATF6 can control the aging through maintaining organelle homeostasis.…”

Section: Atf6mentioning

confidence: 99%

ER Stress-Sensor Proteins and ER-Mitochondrial Crosstalk—Signaling Beyond (ER) Stress Response

Kumar

Maity

2021

Biomolecules

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Recent studies undoubtedly show the importance of inter organellar connections to maintain cellular homeostasis. In normal physiological conditions or in the presence of cellular and environmental stress, each organelle responds alone or in coordination to maintain cellular function. The Endoplasmic reticulum (ER) and mitochondria are two important organelles with very specialized structural and functional properties. These two organelles are physically connected through very specialized proteins in the region called the mitochondria-associated ER membrane (MAM). The molecular foundation of this relationship is complex and involves not only ion homeostasis through the shuttling of calcium but also many structural and apoptotic proteins. IRE1alpha and PERK are known for their canonical function as an ER stress sensor controlling unfolded protein response during ER stress. The presence of these transmembrane proteins at the MAM indicates its potential involvement in other biological functions beyond ER stress signaling. Many recent studies have now focused on the non-canonical function of these sensors. In this review, we will focus on ER mitochondrial interdependence with special emphasis on the non-canonical role of ER stress sensors beyond ER stress.

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“…Moreover, ATF6 can regulate lipid biosynthesis and ER expansion suggesting a possible interplay in MAM-mediated lipid homeostasis and ER-mitochondrial physiology ( Bommiasamy et al, 2009 ). Most recently, ATF6 has also been implicated in ER-mitochondrial Ca 2+ homeostasis ( Burkewitz et al, 2020 ).…”

Section: Mitochondria-associated Endoplasmic Reticulum Membranesmentioning

confidence: 99%

Cal‘MAM’ity at the Endoplasmic Reticulum-Mitochondrial Interface: A Potential Therapeutic Target for Neurodegeneration and Human Immunodeficiency Virus-Associated Neurocognitive Disorders

2021

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The endoplasmic reticulum (ER) is a multifunctional organelle and serves as the primary site for intracellular calcium storage, lipid biogenesis, protein synthesis, and quality control. Mitochondria are responsible for producing the majority of cellular energy required for cell survival and function and are integral for many metabolic and signaling processes. Mitochondria-associated ER membranes (MAMs) are direct contact sites between the ER and mitochondria that serve as platforms to coordinate fundamental cellular processes such as mitochondrial dynamics and bioenergetics, calcium and lipid homeostasis, autophagy, apoptosis, inflammation, and intracellular stress responses. Given the importance of MAM-mediated mechanisms in regulating cellular fate and function, MAMs are now known as key molecular and cellular hubs underlying disease pathology. Notably, neurons are uniquely susceptible to mitochondrial dysfunction and intracellular stress, which highlights the importance of MAMs as potential targets to manipulate MAM-associated mechanisms. However, whether altered MAM communication and connectivity are causative agents or compensatory mechanisms in disease development and progression remains elusive. Regardless, exploration is warranted to determine if MAMs are therapeutically targetable to combat neurodegeneration. Here, we review key MAM interactions and proteins both in vitro and in vivo models of Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. We further discuss implications of MAMs in HIV-associated neurocognitive disorders (HAND), as MAMs have not yet been explored in this neuropathology. These perspectives specifically focus on mitochondrial dysfunction, calcium dysregulation and ER stress as notable MAM-mediated mechanisms underlying HAND pathology. Finally, we discuss potential targets to manipulate MAM function as a therapeutic intervention against neurodegeneration. Future investigations are warranted to better understand the interplay and therapeutic application of MAMs in glial dysfunction and neurotoxicity.

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Atf-6 Regulates Lifespan through ER-Mitochondrial Calcium Homeostasis

Cited by 52 publications

References 46 publications

Role of Unfolded Protein Response and Endoplasmic Reticulum-Associated Degradation by Repeated Exposure to Inhalation Anesthetics in Caenorhabditis elegans

Role of Unfolded Protein Response and Endoplasmic Reticulum-Associated Degradation by Repeated Exposure to Inhalation Anesthetics in Caenorhabditis elegans

ER Stress-Sensor Proteins and ER-Mitochondrial Crosstalk—Signaling Beyond (ER) Stress Response

Cal‘MAM’ity at the Endoplasmic Reticulum-Mitochondrial Interface: A Potential Therapeutic Target for Neurodegeneration and Human Immunodeficiency Virus-Associated Neurocognitive Disorders

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