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Article: Mapping Stress-Responsive Signaling Pathways Induced by Mitochondrial Proteostasis Perturbations.

Madrazo, Nicole / Khattar, Zinia / Powers, Evan T / Rosarda, Jessica D / Wiseman, R Luke

bioRxiv : the preprint server for biology

2024

Abstract: Imbalances in mitochondrial proteostasis are associated with pathologic mitochondrial dysfunction implicated in etiologically-diverse diseases. This has led to considerable interest in defining the biological mechanisms responsible for regulating ... ...

Abstract	Imbalances in mitochondrial proteostasis are associated with pathologic mitochondrial dysfunction implicated in etiologically-diverse diseases. This has led to considerable interest in defining the biological mechanisms responsible for regulating mitochondria in response to mitochondrial stress. Numerous stress responsive signaling pathways have been suggested to regulate mitochondria in response to proteotoxic stress, including the integrated stress response (ISR), the heat shock response (HSR), and the oxidative stress response (OSR). Here, we define the specific stress signaling pathways activated in response to mitochondrial proteostasis stress by monitoring the expression of sets of genes regulated downstream of each of these signaling pathways in published Perturb-seq datasets from K562 cells CRISPRi-depleted of individual mitochondrial proteostasis factors. Interestingly, we find that the ISR is preferentially activated in response to mitochondrial proteostasis stress, with no other pathway showing significant activation. Further expanding this study, we show that broad depletion of mitochondria-localized proteins similarly shows preferential activation of the ISR relative to other stress-responsive signaling pathways. These results both establish our gene set profiling approach as a viable strategy to probe stress responsive signaling pathways induced by perturbations to specific organelles and identify the ISR as the predominant stress-responsive signaling pathway activated in response to mitochondrial proteostasis disruption.
Language	English
Publishing date	2024-02-01
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.01.30.577830
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Article ; Online: Mapping stress-responsive signaling pathways induced by mitochondrial proteostasis perturbations.

Madrazo, Nicole / Khattar, Zinia / Powers, Evan T / Rosarda, Jessica D / Wiseman, R Luke

Molecular biology of the cell

2024 Volume 35, Issue 5, Page(s) ar74

Abstract: Imbalances in mitochondrial proteostasis are associated with pathologic mitochondrial dysfunction implicated in etiologically diverse diseases. This has led to considerable interest in defining the mechanisms responsible for regulating mitochondria in ... ...

Abstract	Imbalances in mitochondrial proteostasis are associated with pathologic mitochondrial dysfunction implicated in etiologically diverse diseases. This has led to considerable interest in defining the mechanisms responsible for regulating mitochondria in response to mitochondrial stress. Numerous stress-responsive signaling pathways have been suggested to regulate mitochondria in response to proteotoxic stress. These include the integrated stress response (ISR), the heat shock response (HSR), and the oxidative stress response (OSR). Here, we define the stress signaling pathways activated in response to chronic mitochondrial proteostasis perturbations by monitoring the expression of sets of genes regulated downstream of each of these signaling pathways in published Perturb-seq datasets from K562 cells CRISPRi-depleted of mitochondrial proteostasis factors. Interestingly, we find that the ISR is preferentially activated in response to chronic, genetically-induced mitochondrial proteostasis stress, with no other pathway showing significant activation. Further, we demonstrate that CRISPRi depletion of other mitochondria-localized proteins similarly shows preferential activation of the ISR relative to other stress-responsive signaling pathways. These results both establish our gene set profiling approach as a viable strategy to probe stress responsive signaling pathways induced by perturbations to specific organelles and identify the ISR as the predominant stress-responsive signaling pathway activated in response to chronic disruption of mitochondrial proteostasis.
MeSH term(s)	Proteostasis/physiology ; Mitochondria/metabolism ; Oxidative Stress ; Signal Transduction/physiology ; Heat-Shock Response ; Mitochondrial Proteins/metabolism
Chemical Substances	Mitochondrial Proteins
Language	English
Publishing date	2024-03-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	1098979-1
ISSN	1939-4586 ; 1059-1524
ISSN (online)	1939-4586
ISSN	1059-1524
DOI	10.1091/mbc.E24-01-0041
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Article ; Online: Psychological Impact of the COVID-19 Pandemic on Canadian Surgical Residents: A Province-Wide Study.

Lie, Jessica J / Huynh, Caroline / Li, Jennifer / Mak, Nicole / Wiseman, Sam M

Journal of surgical education

2024 Volume 81, Issue 4, Page(s) 486–494

Abstract: Objectives: The objective of this study was to evaluate the psychological impact of the COVID-19 pandemic on surgical residents.: Design: An online survey was distributed evaluating multiple domains: demographics, health and socioeconomic factors, ... ...

Abstract	Objectives: The objective of this study was to evaluate the psychological impact of the COVID-19 pandemic on surgical residents. Design: An online survey was distributed evaluating multiple domains: demographics, health and socioeconomic factors, clinical experience, educational experience, and psychological outcomes. The Mayo Clinic Resident Well-Being Index (RWBI) was used as a validated measure of resident mental health. Setting and participants: Surgical residents from University of British Columbia's surgical residency programs. Results: A total of 31/86 surgical residents responded to the survey. Of which, 57% and 46% reported feeling burned out or depressed, respectively. Residents who were concerned about personal protective equipment supply and who lived with family members with comorbidities had a higher risk of depression (p = 0.03, p = 0.04). The median Mayo Clinic Resident Well-Being Index was 2.5, higher than the median of 2 observed in the United States national survey of residents. Conclusions: The pandemic had a considerable negative impact on the psychological well-being of surgical residents.
MeSH term(s)	Humans ; United States ; COVID-19/epidemiology ; Internship and Residency ; Pandemics ; Canada ; Surveys and Questionnaires ; Burnout, Professional/epidemiology
Language	English
Publishing date	2024-02-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	2277538-9
ISSN	1878-7452 ; 1931-7204
ISSN (online)	1878-7452
ISSN	1931-7204
DOI	10.1016/j.jsurg.2023.12.013
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Article: Impact of vision impairment on discharge destination for patients with hip fracture.

Tollette, Jacarri / Heh, Victor / Wiseman, Jessica M / Quatman-Yates, Catherine C / Moroi, Sayoko / Quatman, Carmen E

Journal of clinical orthopaedics and trauma

2024 Volume 50, Page(s) 102377

Abstract: Introduction: Vision impairment (VI) due to low vision or blindness is a major sensory health problem affecting quality of life and contributing to increased risk of falls and hip fractures (HF). Up to 60% of patients with hip fracture have VI, and VI ... ...

Abstract	Introduction: Vision impairment (VI) due to low vision or blindness is a major sensory health problem affecting quality of life and contributing to increased risk of falls and hip fractures (HF). Up to 60% of patients with hip fracture have VI, and VI increases further susceptibility to falls due to mobility challenges after HF. We sought to determine if VI affects discharge destination for patients with HF. Materials and methods: Cross-sectional analysis of 2015 Inpatient Medicare claims was performed and VI, blindness/low vision), HF and HF surgery were identified using ICD-9, and ICD-10 codes. Patients who sustained a HF with a diagnosis of VI were categorized as HF + VI. The outcome measure was discharge destination of home, skilled nursing facility (SNF), long-term care facility (LTCF) or other. Results: During the one-year ascertainment of inpatient claims, there were 10,336 total HF patients, 66.82% female, 91.21% non-Hispanic white with mean (standard deviation) age 82.3 (8.2) years. There was an age-related increase in diagnosis of VI with 1.49% (29/1941) of patients aged 65-74, 1.76% (63/3574) of patients aged 75-84, and 2.07% (100/4821) of patients aged 85 and older. The prevalence of VI increased with age, representing 1.5% (29/1941) of adults aged 65-74, 1.8% (63/3574) of adults aged 75-84, and 2.1% (100/4821) of adults aged 85 and older. The age-related increase in VI was not significant (P = 0.235). Patients with HF were most commonly discharged to a SNF (64.46%), followed by 'Other' (25.70%), home (7.15%), and LTCF (2.67%). VI was not associated with discharge destination. Male gender, Black race, systemic complications, and late postoperative discharge significantly predicted discharge to LTCF with odds ratios (95%CI) 1.42 (1.07-1.89), 1.90 (1.13-3.18), 2.27 (1.66-3.10), and 1.73 (1.25-2.39) respectively. Conclusions: The co-morbid presence of VI was not associated with altered discharge destinations to home, skilled nursing facility, LTCF or other setting.
Language	English
Publishing date	2024-02-27
Publishing country	India
Document type	Journal Article
ZDB-ID	2596956-0
ISSN	2213-3445 ; 0976-5662
ISSN (online)	2213-3445
ISSN	0976-5662
DOI	10.1016/j.jcot.2024.102377
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Article: Simulating traumatic brain injury

Basit, Raja Haseeb / Wiseman, Jessica / Chowdhury, Farhana / Chari, Divya Maitreyi

Neural regeneration research

2022 Volume 18, Issue 2, Page(s) 289–292

Abstract: Traumatic brain injuries are serious clinical incidents associated with some of the poorest outcomes in neurological practice. Coupled with the limited regenerative capacity of the brain, this has significant implications for patients, carers, and ... ...

Abstract	Traumatic brain injuries are serious clinical incidents associated with some of the poorest outcomes in neurological practice. Coupled with the limited regenerative capacity of the brain, this has significant implications for patients, carers, and healthcare systems, and the requirement for life-long care in some cases. Clinical treatment currently focuses on limiting the initial neural damage with long-term care/support from multidisciplinary teams. Therapies targeting neuroprotection and neural regeneration are not currently available but are the focus of intensive research. Biomaterial-based interventions are gaining popularity for a range of applications including biomolecule and drug delivery, and to function as cellular scaffolds. Experimental investigations into the development of such novel therapeutics for traumatic brain injury will be critically underpinned by the availability of appropriate high throughput, facile, ethically viable, and pathomimetic biological model systems. This represents a significant challenge for researchers given the pathological complexity of traumatic brain injury. Specifically, there is a concerted post-injury response mounted by multiple neural cell types which includes microglial activation and astroglial scarring with the expression of a range of growth inhibitory molecules and cytokines in the lesion environment. Here, we review common models used for the study of traumatic brain injury (ranging from live animal models to in vitro systems), focusing on penetrating traumatic brain injury models. We discuss their relative advantages and drawbacks for the developmental testing of biomaterial-based therapies.
Language	English
Publishing date	2022-08-24
Publishing country	India
Document type	Journal Article ; Review
ZDB-ID	2388460-5
ISSN	1876-7958 ; 1673-5374
ISSN (online)	1876-7958
ISSN	1673-5374
DOI	10.4103/1673-5374.346465
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Article ; Online: Teaching Leadership…More than Just White Men.

Hartzell, Joshua D / Servey, Jessica T / Hunt, Guen / Wiseman, Melanie / Gibson, Kim

The American journal of medicine

2022 Volume 135, Issue 8, Page(s) 929–930

MeSH term(s)	Humans ; Leadership ; Teaching
Language	English
Publishing date	2022-03-18
Publishing country	United States
Document type	Editorial
ZDB-ID	80015-6
ISSN	1555-7162 ; 1873-2178 ; 0002-9343 ; 1548-2766
ISSN (online)	1555-7162 ; 1873-2178
ISSN	0002-9343 ; 1548-2766
DOI	10.1016/j.amjmed.2022.02.033
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Article: Pharmacologic Activation of a Compensatory Integrated Stress Response Kinase Promotes Mitochondrial Remodeling in PERK-deficient Cells.

Perea, Valerie / Baron, Kelsey R / Dolina, Vivian / Aviles, Giovanni / Rosarda, Jessica D / Guo, Xiaoyan / Kampmann, Martin / Wiseman, R Luke

bioRxiv : the preprint server for biology

2023

Abstract: The integrated stress response (ISR) comprises the eIF2α kinases PERK, GCN2, HRI, and PKR, which induce translational and transcriptional signaling in response to diverse insults. Deficiencies in PERK signaling lead to mitochondrial dysfunction and ... ...

Abstract	The integrated stress response (ISR) comprises the eIF2α kinases PERK, GCN2, HRI, and PKR, which induce translational and transcriptional signaling in response to diverse insults. Deficiencies in PERK signaling lead to mitochondrial dysfunction and contribute to the pathogenesis of numerous diseases. We define the potential for pharmacologic activation of compensatory eIF2α kinases to rescue ISR signaling and promote mitochondrial adaptation in PERK-deficient cells. We show that the HRI activator BtdCPU and GCN2 activator halofuginone promote ISR signaling and rescue ER stress sensitivity in PERK-deficient cells. However, BtdCPU induces mitochondrial depolarization, leading to mitochondrial fragmentation and activation of the OMA1-DELE1-HRI signaling axis. In contrast, halofuginone promotes mitochondrial elongation and adaptive mitochondrial respiration, mimicking regulation induced by PERK. This shows halofuginone can compensate for deficiencies in PERK signaling and promote adaptive mitochondrial remodeling, highlighting the potential for pharmacologic ISR activation to mitigate mitochondrial dysfunction and motivating the pursuit of highly-selective ISR activators.
Language	English
Publishing date	2023-05-17
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.03.11.532186
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Article ; Online: Pharmacologic activation of a compensatory integrated stress response kinase promotes mitochondrial remodeling in PERK-deficient cells.

Perea, Valerie / Baron, Kelsey R / Dolina, Vivian / Aviles, Giovanni / Kim, Grace / Rosarda, Jessica D / Guo, Xiaoyan / Kampmann, Martin / Wiseman, R Luke

Cell chemical biology

2023 Volume 30, Issue 12, Page(s) 1571–1584.e5

Abstract	The integrated stress response (ISR) comprises the eIF2α kinases PERK, GCN2, HRI, and PKR, which induce translational and transcriptional signaling in response to diverse insults. Deficiencies in PERK signaling lead to mitochondrial dysfunction and contribute to the pathogenesis of numerous diseases. We define the potential for pharmacologic activation of compensatory eIF2α kinases to rescue ISR signaling and promote mitochondrial adaptation in PERK-deficient cells. We show that the HRI activator BtdCPU and GCN2 activator halofuginone promote ISR signaling and rescue ER stress sensitivity in PERK-deficient cells. However, BtdCPU induces mitochondrial depolarization, leading to mitochondrial fragmentation and activation of the OMA1-DELE1-HRI signaling axis. In contrast, halofuginone promotes mitochondrial elongation and adaptive mitochondrial respiration, mimicking regulation induced by PERK. This shows halofuginone can compensate for deficiencies in PERK signaling and promote adaptive mitochondrial remodeling, highlighting the potential for pharmacologic ISR activation to mitigate mitochondrial dysfunction and motivating the pursuit of highly selective ISR activators.
MeSH term(s)	eIF-2 Kinase/genetics ; eIF-2 Kinase/metabolism ; Mitochondria/metabolism ; Mitochondrial Diseases/metabolism ; Phosphorylation ; Protein Processing, Post-Translational ; Signal Transduction ; Animals ; Mice
Chemical Substances	eIF-2 Kinase (EC 2.7.11.1)
Language	English
Publishing date	2023-11-02
Publishing country	United States
Document type	Journal Article
ISSN	2451-9448
ISSN (online)	2451-9448
DOI	10.1016/j.chembiol.2023.10.006
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Article ; Online: Imbalanced unfolded protein response signaling contributes to 1-deoxysphingolipid retinal toxicity.

Rosarda, Jessica D / Giles, Sarah / Harkins-Perry, Sarah / Mills, Elizabeth A / Friedlander, Martin / Wiseman, R Luke / Eade, Kevin T

Nature communications

2023 Volume 14, Issue 1, Page(s) 4119

Abstract: The accumulation of atypical, cytotoxic 1-deoxysphingolipids (1-dSLs) has been linked to retinal diseases such as diabetic retinopathy and Macular Telangiectasia Type 2. However, the molecular mechanisms by which 1-dSLs induce toxicity in retinal cells ... ...

Abstract	The accumulation of atypical, cytotoxic 1-deoxysphingolipids (1-dSLs) has been linked to retinal diseases such as diabetic retinopathy and Macular Telangiectasia Type 2. However, the molecular mechanisms by which 1-dSLs induce toxicity in retinal cells remain poorly understood. Here, we integrate bulk and single-nucleus RNA-sequencing to define biological pathways that modulate 1-dSL toxicity in human retinal organoids. Our results demonstrate that 1-dSLs differentially activate signaling arms of the unfolded protein response (UPR) in photoreceptor cells and Müller glia. Using a combination of pharmacologic activators and inhibitors, we show that sustained PERK signaling through the integrated stress response (ISR) and deficiencies in signaling through the protective ATF6 arm of the UPR are implicated in 1-dSL-induced photoreceptor toxicity. Further, we demonstrate that pharmacologic activation of ATF6 mitigates 1-dSL toxicity without impacting PERK/ISR signaling. Collectively, our results identify new opportunities to intervene in 1-dSL linked diseases through targeting different arms of the UPR.
MeSH term(s)	Humans ; Diabetic Retinopathy ; Sphingolipids ; Retinal Telangiectasis ; Unfolded Protein Response
Chemical Substances	1-deoxysphingolipid ; Sphingolipids
Language	English
Publishing date	2023-07-11
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-39775-w
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Article ; Online: Covalent Targeting As a Common Mechanism for Inhibiting NLRP3 Inflammasome Assembly.

Stanton, Caroline / Sun, Jie / Nutsch, Kayla / Rosarda, Jessica D / Nguyen, Thu / Li-Ma, Chloris / Njomen, Evert / Melillo, Bruno / Kutseikin, Sergei / Saez, Enrique / Cravatt, Benjamin F / Teijaro, John R / Wiseman, R Luke / Bollong, Michael J

ACS chemical biology

2024 Volume 19, Issue 2, Page(s) 254–265

Abstract: The NLRP3 inflammasome is a cytosolic protein complex important for the regulation and secretion of inflammatory cytokines, including IL-1β and IL-18. Aberrant overactivation of NLRP3 is implicated in numerous inflammatory disorders. However, the ... ...

Abstract	The NLRP3 inflammasome is a cytosolic protein complex important for the regulation and secretion of inflammatory cytokines, including IL-1β and IL-18. Aberrant overactivation of NLRP3 is implicated in numerous inflammatory disorders. However, the activation and regulation of NLRP3 inflammasome signaling remain poorly understood, limiting our ability to develop pharmacologic approaches to target this important inflammatory complex. Here, we developed and implemented a high-throughput screen to identify compounds that inhibit the inflammasome assembly and activity. From this screen, we identify and profile inflammasome inhibition of 20 new covalent compounds across nine different chemical scaffolds, as well as many known inflammasome covalent inhibitors. Intriguingly, our results indicate that NLRP3 possesses numerous reactive cysteines on multiple domains whose covalent targeting blocks the activation of this inflammatory complex. Specifically, focusing on compound VLX1570, which possesses multiple electrophilic moieties, we demonstrate that this compound allows covalent, intermolecular cross-linking of NLRP3 cysteines to inhibit inflammasome assembly. Our results, along with the recent identification of numerous covalent molecules that inhibit NLRP3 inflammasome activation, further support the continued development of electrophilic compounds that target reactive cysteine residues on NLRP3 to regulate its activation and activity.
MeSH term(s)	Inflammasomes/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Signal Transduction ; Cytokines ; Interleukin-1beta/metabolism
Chemical Substances	Inflammasomes ; NLR Family, Pyrin Domain-Containing 3 Protein ; Cytokines ; Interleukin-1beta
Language	English
Publishing date	2024-01-10
Publishing country	United States
Document type	Journal Article
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/acschembio.3c00330
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