The HRI branch of the integrated stress response selectively triggers mitophagy

Creators: Chakrabarty, Yogaditya; Yang, Zheng; Chen, Hsiuchen; Chan, David C.¹

1. California Institute of Technology

Abstract

To maintain mitochondrial homeostasis, damaged or excessive mitochondria are culled in coordination with the physiological state of the cell. The integrated stress response (ISR) is a signaling network that recognizes diverse cellular stresses, including mitochondrial dysfunction. Because the four ISR branches converge to common outputs, it is unclear whether mitochondrial stress detected by this network can regulate mitophagy, the autophagic degradation of mitochondria. Using a whole-genome screen, we show that the heme-regulated inhibitor (HRI) branch of the ISR selectively induces mitophagy. Activation of the HRI branch results in mitochondrial localization of phosphorylated eukaryotic initiation factor 2, which we show is sufficient to induce mitophagy. The HRI mitophagy pathway operates in parallel with the mitophagy pathway controlled by the Parkinson’s disease related genes PINK1 and PARKIN and is mechanistically distinct. Therefore, HRI repurposes machinery that is normally used for translational initiation to trigger mitophagy in response to mitochondrial damage.

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Acknowledgement

We are grateful to A. Merchan, J. Repogle, J. Weissman, K. Page, R. She, and R. Voorhees for encouragement and advice on CRISPRi screening; D. Perez, J. Tijerina, and R. Diamond (Caltech Flow Cytometry and Cell Sorting Facility) for support with flow cytometry and FACS experiments; and I. Antoshechkin (Millard and Muriel Jacobs Genetics and Genomics Laboratory, Caltech) for support with next-generation sequencing. We thank the following investigators for contribution of important reagents: L. Jae, S. Yamashita, K. Yamano, N. Matsuda, G. Varuzhanyan, R. Youle, A. Ting, M. Moore, D. Ron, and J. Lippincott-Schwartz. We thank members of the Chan lab for helpful discussions and comments on the manuscript. This work was funded by the National Institutes of Health grant R35 GM127147 (D.C.C.).

Contributions

Conceptualization, Y.C. and D.C.C.; methodology, Y.C., Z.Y., and H.C.; investigation, Y.C., Z.Y., and H.C.; funding acquisition, D.C.C.; supervision, D.C.C.; writing – original draft, Y.C. and D.C.C.; writing – review & editing, Y.C., D.C.C., Z.Y., and H.C.

Conflict of Interest

The authors declare no competing interests.

Data Availability

No additional resources were generated by this study.

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