Mitochondrial dysfunction is signaled to the integrated stress response by OMA1, DELE1 and HRI

Guo, Xiaoyan; Aviles, Giovanni; Liu, Yi; Tian, Ruilin; Unger, Bret A.; Lin, Yu-Hsiu T.; Wiita, Arun P.; Xu, Ke; Correia, Maria Almira; Kampmann, Martin

doi:10.1101/715896

Cited by 18 publications

(29 citation statements)

References 64 publications

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“…While there was some variation in the magnitude of transcriptional responses (e.g., proteostatic injury drove an especially strong ISR activation), nuclear transcriptional responses generally failed to discriminate genetic perturbations by function. Although this result was broadly consistent with recent literature that has highlighted the role of the ISR as response to mitochondrial stress (49)(50)(51)(52)(53), the lack of functional specificity of the transcriptional response was puzzling in light of: (i) the multifaceted roles of mitochondria in diverse processes such as respiration, intermediary metabolism, iron-sulfur cluster biogenesis, and apoptosis and (ii) the high-resolution separation of cytosolic perturbations by transcriptional response in our data described above.…”

Section: Discovery Of Stress-specific Regulation Of the Mitochondrial Genomesupporting

confidence: 89%

Mapping information-rich genotype-phenotype landscapes with genome-scale Perturb-seq

Replogle¹,

Saunders²,

Pogson³

et al. 2021

Preprint

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A central goal of genetics is to define the relationships between genotypes and phenotypes. High-content phenotypic screens such as Perturb-seq (pooled CRISPR-based screens with single-cell RNA-sequencing readouts) enable massively parallel functional genomic mapping but, to date, have been used at limited scales. Here, we perform genome-scale Perturb-seq targeting all expressed genes with CRISPR interference (CRISPRi) across >2.5 million human cells and present a framework to power biological discovery with the resulting genotype-phenotype map. We use transcriptional phenotypes to predict the function of poorly-characterized genes, uncovering new regulators of ribosome biogenesis (including CCDC86, ZNF236, and SPATA5L1), transcription (C7orf26), and mitochondrial respiration (TMEM242). In addition to assigning gene function, single-cell transcriptional phenotypes allow for in-depth dissection of complex cellular phenomena – from RNA processing to differentiation. We leverage this ability to systematically identify the genetic drivers and consequences of aneuploidy and to discover an unanticipated layer of stress-specific regulation of the mitochondrial genome. Our information-rich genotype-phenotype map reveals a multidimensional portrait of gene function and cellular behavior.

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Section: Discovery Of Stress-specific Regulation Of the Mitochondrial Genomesupporting

confidence: 89%

Mapping information-rich genotype-phenotype landscapes with genome-scale Perturb-seq

Replogle¹,

Saunders²,

Pogson³

et al. 2021

Preprint

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show abstract

“…Alternatively, inhibition of OXPHOS could initiate UPR that takes over to repress lastresort ER-phagy. Consistently, mitochondrial dysfunction was reported to trigger the integrated stress response (ISR) which converges with the UPR pathway, further highlighting the complex cross-talk between the two organelles (Guo et al, 2019). Cellular energy levels are regulated by multiple energy sensing mechanisms that have complex roles during general autophagy (Egan et al, 2011;Herzig and Shaw, 2018;Kim et al, 2011), and the interplay between mitochondrial metabolism and ER homeostasis will no doubt involve a rich set of pathways for future investigation.…”

Section: Discussionmentioning

confidence: 89%

A Genome-wide ER-phagy Screen Highlights Key Roles of Mitochondrial Metabolism and ER-Resident UFMylation

Liang

Lingeman

Luong

et al. 2020

Cell

202

240

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Selective autophagy of organelles is critical for cellular differentiation, homeostasis, and organismal health. Autophagy of the ER (ER-phagy) is implicated in human neuropathy but is poorly understood beyond a few autophagosomal receptors and remodelers. By using an ER-phagy reporter and genome-wide CRISPRi screening, we identified 200 high-confidence human ER-phagy factors. Two pathways were unexpectedly required for ER-phagy. First, reduced mitochondrial metabolism represses ERphagy, which is opposite of general autophagy and is independent of AMPK. Second, ER-localized UFMylation is required for ER-phagy to repress the unfolded protein response via IRE1a. The UFL1 ligase is brought to the ER surface by DDRGK1 to UFMylate RPN1 and RPL26 and preferentially targets ER sheets for degradation, analogous to PINK1-Parkin regulation during mitophagy. Our data provide insight into the cellular logic of ER-phagy, reveal parallels between organelle autophagies, and provide an entry point to the relatively unexplored process of degrading the ER network. UFMylation

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“…When heme concentrations are low, HRI is activated. Although HRI was long thought to have a specialized role in erythroid cells dedicated to hemoglobin synthesis (40), it is now recognized that HRI is widely expressed in several cell types and organs (41) and responds to multiple other forms of cellular cell stress, such as oxidative and mitochondrial stress, heat shock, and cytosolic protein aggregation (42).…”

Section: Four Kinases Converge On Eif2 To Activate the Isrmentioning

confidence: 99%

The integrated stress response: From mechanism to disease

Costa-Mattioli

Walter

2020

Science

889

816

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Protein quality control is essential for the proper function of cells and the organisms that they make up. The resulting loss of proteostasis, the processes by which the health of the cell’s proteins is monitored and maintained at homeostasis, is associated with a wide range of age-related human diseases. Here, we highlight how the integrated stress response (ISR), a central signaling network that responds to proteostasis defects by tuning protein synthesis rates, impedes the formation of long-term memory. In addition, we address how dysregulated ISR signaling contributes to the pathogenesis of complex diseases, including cognitive disorders, neurodegeneration, cancer, diabetes, and metabolic disorders. The development of tools through which the ISR can be modulated promises to uncover new avenues to diminish pathologies resulting from it for clinical benefit.

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Mitochondrial dysfunction is signaled to the integrated stress response by OMA1, DELE1 and HRI

Cited by 18 publications

References 64 publications

Mapping information-rich genotype-phenotype landscapes with genome-scale Perturb-seq

Mapping information-rich genotype-phenotype landscapes with genome-scale Perturb-seq

A Genome-wide ER-phagy Screen Highlights Key Roles of Mitochondrial Metabolism and ER-Resident UFMylation

The integrated stress response: From mechanism to disease

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