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bioRxiv · 10.1101/659128

Impaired peroxisomal import in Drosophila hepatocyte-like cells induces cardiac dysfunction through the pro-inflammatory cytokine Upd3

Huang, K.·Miao, T.·Chang, K.·Kang, P.·Jiang, Q.·Simmonds, A. J.·Di Cara, F.·Bai, H.
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Abstract

Age is a major risk factor for cardiovascular diseases. Currently, the non-autonomous regulation of age-related cardiac dysfunction is poorly understood. In the present study, we discover that age-dependent induction of cytokine unpaired 3 (Upd3) in Drosophila oenocytes (hepatocyte-like cells), due to a dampened peroxisomal import function, is the primary non-autonomous mechanism for elevated arrhythmicity in old hearts. We show that Upd3 is significantly up-regulated (52-fold) 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. Intriguingly, oenocyte-specific over-expression of Pex5, the key peroxisomal import receptor, restores peroxisomal import, blocks age-related Upd3 induction, and alleviates aging- and paraquat-induced cardiac arrhythmicity. Thus, our studies identify an important role of the evolutionarily conserved pro-inflammatory cytokine signaling and hepatocyte-specific peroxisomal import in mediating non-autonomous regulation of cardiac aging.

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Huang, K., Miao, T., Chang, K., Kang, P., Jiang, Q., Simmonds, A. J., Di Cara, F., Bai, H.. 2019-06-03. Impaired peroxisomal import in Drosophila hepatocyte-like cells induces cardiac dysfunction through the pro-inflammatory cytokine Upd3. https://doi.org/10.1101/659128

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