Impaired peroxisomal import in Drosophila oenocytes causes cardiac dysfunction by inducing upd3 as a peroxikine

Huang, Kerui; Miao, T.; Chang, Kai; Kim, Jinoh; Kang, Ping; Jiang, Qiuhan; Simmonds, Andrew; Cara, Francesca Di; Bai, Hua

doi:10.1038/s41467-020-16781-w

Cited by 26 publications

(44 citation statements)

References 70 publications

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“…Oenocytes are hepatocyte-like cells that are highly enriched with peroxisomes 19, 33 . In addition, the oenocyte peroxisome was identified as an important regulator for age-related production of inflammatory factor, unpaired 3 (upd3) 19 , which could dampen cardiac function non-autonomously. To study cellular responses induced by peroxisomal stress, we performed transcriptomic analysis from Drosophila oenocytes and human cell cultures.…”

Section: Resultsmentioning

confidence: 99%

“…Consistently, our translatomic study shows that the majority of peroxisome genes are downregulated in aged fly oenocytes 18 . Our previous study identified that peroxisome import activities in fly oenocytes can non-autonomously regulate cardiac arrhythmia during aging 19 . Several other studies have also implicated that peroxisome is involved in longevity 20–22 .…”

Section: Introductionmentioning

confidence: 99%

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Peroxisome import stress impairs ribosome biogenesis and induces integrative stress response through eIF2α phosphorylation

Huang

Bai

2020

Preprint

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Peroxisome biogenesis diseases (PBDs) are characterized by global defects in peroxisomal function and can result in severe brain, liver, kidney, and bone malfunctions. PBDs are due to mutations in peroxisome biogenesis factors (PEX genes) that are responsible for peroxisome assembly and function. There is increasing evidence suggesting that peroxisome import functions decline during aging. The transcriptome profiling of peroxisome import defects is still lacking. To identify conserved responses, we undertook a bioinformatic transcriptomic analysis on Drosophila oenocyte specific Pex1, Pex12 and Pex5 knockdowns. In addition, we performed analysis on human cells with induced peroxisome import stress. We uncovered that oenocyte-specific Pex1, Pex12 and Pex5 have distinct transcriptional profiles with each other. Using gene set enrichment analysis (GSEA), we identified protein processing in endoplasmic reticulum pathway, specifically ER-associated protein degradation (ERAD) pathway is enriched and induced in all PEX knockdowns in Drosophila. Moreover, we uncovered decreased expression in ribosome biogenesis genes in flies and human cells. Indeed, we identified a stall at the 5’-ETS cleavage sites during the ribosome biogenesis and impaired 40S small ribosomal export in both flies and human. Our data indicates an unexpected link between peroxisome and ribosome biogenesis. Our results suggest that reduced ribosome biogenesis could be conserved cellular response to reduce peroxisome import stress.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Peroxisome import stress impairs ribosome biogenesis and induces integrative stress response through eIF2α phosphorylation

Huang

Bai

2020

Preprint

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“…Cannabinoid-2 receptor activation markedly improved hepatic/myocardial inflammation, decreased serum TNF-α level, and cardiac dysfunction, underlining the importance of inflammatory mediators in the pathology of this disease 113 . Hepatocyte-specific knockout of IL-6 was sufficient to block aging-induced cardiac arrhythmia in a fruit fly model 114 . In addition to the characterized linking function of adropin 19 and fetuin 33 , a recent study reported that alpha-1-microglobulin (AMBP) exacerbated inflammation and disturbed hepatic fibrotic repair after myocardial infarction through activating Akt, NF-κB, and ERK signaling and promoting macrophage migration and polarization 115 .…”

Section: Communications Between the Liver And Other Major Organsmentioning

confidence: 97%

Organ-organ communication: The liver's perspective

Wang¹,

So²,

Xiao³

et al. 2021

Theranostics

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Communication between organs participates in most physiological and pathological events. Owing to the importance of precise coordination among the liver and virtually all organs in the body for the maintenance of homeostasis, many hepatic disorders originate from impaired organ-organ communication, resulting in concomitant pathological phenotypes of distant organs. Hepatokines are proteins that are predominantly secreted from the liver, and many hepatokines and several signaling proteins have been linked to diseases of other organs, such as the heart, muscle, bone, and eyes. Although liver-centered interorgan communication has been proposed in both basic and clinical studies, to date, the regulatory mechanisms of hepatokine production, secretion, and reciprocation with signaling factors from other organs are obscure. Whether other hormones and cytokines are involved in such communication also warrants investigation. Herein, we summarize the current knowledge of organ-organ communication phenotypes in a variety of diseases and the possible involvement of hepatokines and/or other important signaling factors. This provides novel insight into the underlying roles and mechanisms of liver-originated signal transduction and, more importantly, the understanding of disease in an integrative view.

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“…Like what was shown in terms of gut homeostasis, peroxisome function plays a role in aging-related inflammation induced cardiac disease. Huang et al (2020) showed that reduction in peroxisome protein import in oenocytes, either experimentally by reduction of factors regulating peroxisome import of Pex1, Pex5, or Pex14 activity, disrupted ROS homeostasis cause by Paraquat treatment or due to aging, led to cardiac arrhythmia ( Huang et al, 2020 ). Notably, the age-related effect on the heart could be suppressed by Gal4 > UAS-Pex5 expression in the oenocytes and that the effect was mediated by induction of the cytokine Unpaired 3, a JAK/STAT ligand ( Hombría et al, 2005 ).…”

Section: Developmental Defects Linked To Peroxisome Dysfunction In mentioning

confidence: 99%

“…Notably, the age-related effect on the heart could be suppressed by Gal4 > UAS-Pex5 expression in the oenocytes and that the effect was mediated by induction of the cytokine Unpaired 3, a JAK/STAT ligand ( Hombría et al, 2005 ). Again, this newly discovered role for peroxisome function seems to be conserved between flies and mammals ( Huang et al, 2020 ).…”

Section: Developmental Defects Linked To Peroxisome Dysfunction In mentioning

confidence: 99%

Rosy Beginnings: Studying Peroxisomes in Drosophila

Pridie

Ueda

Simmonds

2020

Front. Cell Dev. Biol.

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Research using the fruit fly Drosophila melanogaster has traditionally focused on understanding how mutations affecting gene regulation or function affect processes linked to animal development. Accordingly, flies have become an essential foundation of modern medical research through repeated contributions to our fundamental understanding of how their homologs of human genes function. Peroxisomes are organelles that metabolize lipids and reactive oxygen species like peroxides. However, despite clear linkage of mutations in human genes affecting peroxisomes to developmental defects, for many years fly models were conspicuously absent from the study of peroxisomes. Now, the few early studies linking the Rosy eye color phenotype to peroxisomes in flies have been joined by a growing body of research establishing novel roles for peroxisomes during the development or function of specific tissues or cell types. Similarly, unique properties of cultured fly Schneider 2 cells have advanced our understanding of how peroxisomes move on the cytoskeleton. Here, we profile how those past and more recent Drosophila studies started to link specific effects of peroxisome dysfunction to organ development and highlight the utility of flies as a model for human peroxisomal diseases. We also identify key differences in the function and proliferation of fly peroxisomes compared to yeast or mammals. Finally, we discuss the future of the fly model system for peroxisome research including new techniques that should support identification of additional tissue specific regulation of and roles for peroxisomes.

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Impaired peroxisomal import in Drosophila oenocytes causes cardiac dysfunction by inducing upd3 as a peroxikine

Cited by 26 publications

References 70 publications

Peroxisome import stress impairs ribosome biogenesis and induces integrative stress response through eIF2α phosphorylation

Peroxisome import stress impairs ribosome biogenesis and induces integrative stress response through eIF2α phosphorylation

Organ-organ communication: The liver's perspective

Rosy Beginnings: Studying Peroxisomes in Drosophila

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