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ResearchIn-Press PreviewOphthalmology Open Access | 10.1172/jci.insight.142254

Mitochondria-dependent phase separation of disease-relevant proteins drives pathological features of age-related macular degeneration

Nilsa La Cunza,1 Li Xuan Tan,1 Thushara Thamban,1 Colin J Germer,1 Gurugirijha Rathnasamy,1 Kimberly Toops,2 and Aparna Lakkaraju1

1Department of Ophthalmology, University of California, San Francisco, San Francisco, United States of America

2Microscopy, Carl Zeiss Microscopy, LLC, White Plains, United States of America

Find articles by La Cunza, N. in: JCI | PubMed | Google Scholar |

1Department of Ophthalmology, University of California, San Francisco, San Francisco, United States of America

2Microscopy, Carl Zeiss Microscopy, LLC, White Plains, United States of America

Find articles by Tan, L. in: JCI | PubMed | Google Scholar

1Department of Ophthalmology, University of California, San Francisco, San Francisco, United States of America

2Microscopy, Carl Zeiss Microscopy, LLC, White Plains, United States of America

Find articles by Thamban, T. in: JCI | PubMed | Google Scholar

1Department of Ophthalmology, University of California, San Francisco, San Francisco, United States of America

2Microscopy, Carl Zeiss Microscopy, LLC, White Plains, United States of America

Find articles by Germer, C. in: JCI | PubMed | Google Scholar |

1Department of Ophthalmology, University of California, San Francisco, San Francisco, United States of America

2Microscopy, Carl Zeiss Microscopy, LLC, White Plains, United States of America

Find articles by Rathnasamy, G. in: JCI | PubMed | Google Scholar

1Department of Ophthalmology, University of California, San Francisco, San Francisco, United States of America

2Microscopy, Carl Zeiss Microscopy, LLC, White Plains, United States of America

Find articles by Toops, K. in: JCI | PubMed | Google Scholar

1Department of Ophthalmology, University of California, San Francisco, San Francisco, United States of America

2Microscopy, Carl Zeiss Microscopy, LLC, White Plains, United States of America

Find articles by Lakkaraju, A. in: JCI | PubMed | Google Scholar

Published April 6, 2021 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.142254.
Copyright © 2021, La Cunza et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published April 6, 2021 - Version history
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Abstract

Age-related macular degeneration (AMD) damages the retinal pigment epithelium (RPE), the tissue that safeguards photoreceptor health, leading to irreversible vision loss. Polymorphisms in cholesterol and complement genes are implicated in AMD, yet mechanisms linking risk variants to RPE injury remain unclear. We sought to determine how allelic variants in the apolipoprotein E cholesterol transporter modulate RPE homeostasis and function. Using live-cell imaging, we show that inefficient cholesterol transport by the AMD risk-associated ApoE2 increases RPE ceramide, leading to autophagic defects and complement-mediated mitochondrial damage. Mitochondrial injury drives redox state-sensitive cysteine-mediated phase separation of ApoE2, forming biomolecular condensates that could nucleate drusen. The protective ApoE4 isoform lacks these cysteines and is resistant to phase separation and condensate formation. In Abca4-/- Stargardt macular degeneration mice, mitochondrial dysfunction induces liquid-liquid phase separation of p62/SQSTM1, a multifunctional protein that regulates autophagy. Drugs that decrease RPE cholesterol or ceramide prevent mitochondrial injury and phase separation in vitro and in vivo. In AMD donor RPE, mitochondrial fragmentation correlates with ApoE and p62 condensates. Our studies demonstrate that major AMD genetic and biological risk pathways converge upon RPE mitochondria, and identify mitochondrial stress-mediated protein phase separation as an important pathogenic mechanism and promising therapeutic target in AMD.

Graphical Abstract
graphical abstract
Supplemental material

View Movie S1 EGFP-LC3 trafficking in Control RPE

View Movie S2 EGFP-LC3 trafficking in RPE with A2E

View Movie S3 EGFP-LC3 trafficking in ApoE2-expressing RPE

View Movie S4 EGFP-LC3 trafficking in ApoE2-expressing RPE with A2E

View Movie S5 EGFP-LC3 trafficking in ApoE3-expressing RPE

View Movie S6 EGFP-LC3 trafficking in ApoE3-expressing RPE with A2E

View Movie S7 EGFP-LC3 trafficking in ApoE4-expressing RPE

View Movie S8 EGFP-LC3 trafficking in ApoE4-expressing RPE with A2E

View

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  • Version 1 (April 6, 2021): In-Press Preview

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