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

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

doi:10.1038/s41467-020-16781-w

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

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

Medicine

Research output: Contribution to journal › Article › peer-review

30 Citations (Scopus)

Abstract

Aging is characterized by a chronic, low-grade inflammation, which is a major risk factor for cardiovascular diseases. It remains poorly understood whether pro-inflammatory factors released from non-cardiac tissues contribute to the non-autonomous regulation of age-related cardiac dysfunction. Here, we report that age-dependent induction of cytokine unpaired 3 (upd3) in Drosophila oenocytes (hepatocyte-like cells) is the primary non-autonomous mechanism for cardiac aging. We show that upd3 is significantly up-regulated in aged oenocytes. Oenocyte-specific knockdown of upd3 is sufficient to block aging-induced cardiac arrhythmia. We further show that the age-dependent induction of upd3 is triggered by impaired peroxisomal import and elevated JNK signaling in aged oenocytes. We term hormonal factors induced by peroxisome dysfunction as peroxikines. Intriguingly, oenocyte-specific overexpression of Pex5, the key peroxisomal import receptor, blocks age-related upd3 induction and alleviates cardiac arrhythmicity. Thus, our studies identify an important role of hepatocyte-specific peroxisomal import in mediating non-autonomous regulation of cardiac aging.

Original language	English
Article number	2943
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-16781-w
Publication status	Published - Dec 1 2020

Bibliographical note

Funding Information:
We thank Bloomington Drosophila Stock Center and Harvard Medical School for fly stocks. We thank Steven X. Hou, Richard Rachubinski, and Kyu-Sun Lee for antibody reagents, and Marc Tatar, Alex Gould, Doug Harrison, Heinrich Jasper, Rolf Bodmer, and Erika Bach for fly stocks. We thank Nancy Braverman for PEX1 mutant cell lines. We also thank Rolf Bodmer and Karen Ocorr for help with fly heartbeat analysis. This work was supported by NIH/NIA R00AG048016, R01AG058741, and AFAR Research Grants for Junior Faculty to H.B., Glenn/AFAR Scholarships for Research in the Biology of Aging to K.H., Alberta Innovates-Collaborative Research and Innovation Opportunities to A.J.S., and Dalhousie Medical Research Foundation to F.D.C.

Publisher Copyright:
© 2020, The Author(s).

ASJC Scopus Subject Areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-020-16781-w

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title = "Impaired peroxisomal import in Drosophila oenocytes causes cardiac dysfunction by inducing upd3 as a peroxikine",

abstract = "Aging is characterized by a chronic, low-grade inflammation, which is a major risk factor for cardiovascular diseases. It remains poorly understood whether pro-inflammatory factors released from non-cardiac tissues contribute to the non-autonomous regulation of age-related cardiac dysfunction. Here, we report that age-dependent induction of cytokine unpaired 3 (upd3) in Drosophila oenocytes (hepatocyte-like cells) is the primary non-autonomous mechanism for cardiac aging. We show that upd3 is significantly up-regulated in aged oenocytes. Oenocyte-specific knockdown of upd3 is sufficient to block aging-induced cardiac arrhythmia. We further show that the age-dependent induction of upd3 is triggered by impaired peroxisomal import and elevated JNK signaling in aged oenocytes. We term hormonal factors induced by peroxisome dysfunction as peroxikines. Intriguingly, oenocyte-specific overexpression of Pex5, the key peroxisomal import receptor, blocks age-related upd3 induction and alleviates cardiac arrhythmicity. Thus, our studies identify an important role of hepatocyte-specific peroxisomal import in mediating non-autonomous regulation of cardiac aging.",

author = "Kerui Huang and Ting Miao and Kai Chang and Jinoh Kim and Ping Kang and Qiuhan Jiang and Simmonds, {Andrew J.} and {Di Cara}, Francesca and Hua Bai",

note = "Funding Information: We thank Bloomington Drosophila Stock Center and Harvard Medical School for fly stocks. We thank Steven X. Hou, Richard Rachubinski, and Kyu-Sun Lee for antibody reagents, and Marc Tatar, Alex Gould, Doug Harrison, Heinrich Jasper, Rolf Bodmer, and Erika Bach for fly stocks. We thank Nancy Braverman for PEX1 mutant cell lines. We also thank Rolf Bodmer and Karen Ocorr for help with fly heartbeat analysis. This work was supported by NIH/NIA R00AG048016, R01AG058741, and AFAR Research Grants for Junior Faculty to H.B., Glenn/AFAR Scholarships for Research in the Biology of Aging to K.H., Alberta Innovates-Collaborative Research and Innovation Opportunities to A.J.S., and Dalhousie Medical Research Foundation to F.D.C. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

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AU - Kang, Ping

AU - Jiang, Qiuhan

AU - Simmonds, Andrew J.

AU - Di Cara, Francesca

AU - Bai, Hua

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N2 - Aging is characterized by a chronic, low-grade inflammation, which is a major risk factor for cardiovascular diseases. It remains poorly understood whether pro-inflammatory factors released from non-cardiac tissues contribute to the non-autonomous regulation of age-related cardiac dysfunction. Here, we report that age-dependent induction of cytokine unpaired 3 (upd3) in Drosophila oenocytes (hepatocyte-like cells) is the primary non-autonomous mechanism for cardiac aging. We show that upd3 is significantly up-regulated in aged oenocytes. Oenocyte-specific knockdown of upd3 is sufficient to block aging-induced cardiac arrhythmia. We further show that the age-dependent induction of upd3 is triggered by impaired peroxisomal import and elevated JNK signaling in aged oenocytes. We term hormonal factors induced by peroxisome dysfunction as peroxikines. Intriguingly, oenocyte-specific overexpression of Pex5, the key peroxisomal import receptor, blocks age-related upd3 induction and alleviates cardiac arrhythmicity. Thus, our studies identify an important role of hepatocyte-specific peroxisomal import in mediating non-autonomous regulation of cardiac aging.

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

Abstract

Bibliographical note

ASJC Scopus Subject Areas

UN SDGs

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