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

Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 101676073 Publication Model: Electronic Cited Medium: Internet ISSN: 2379-3708 (Electronic) Linking ISSN: 23793708 NLM ISO Abbreviation: JCI Insight Subsets: MEDLINE

Original Publication: Ann Arbor, Michigan : American Society for Clinical Investigation, [2016]-

Biomolecular Condensates/*metabolism ; Ceramides/*metabolism ; Cholesterol/*metabolism ; Macular Degeneration/*metabolism ; Mitochondria/*metabolism ; Retinal Pigment Epithelium/*metabolism ; Sequestosome-1 Protein/*metabolism; Animals ; Apolipoprotein E2/genetics ; Apolipoprotein E4/genetics ; Autophagy/physiology ; Biomolecular Condensates/pathology ; Complement System Proteins/metabolism ; Intravital Microscopy ; Macular Degeneration/genetics ; Macular Degeneration/pathology ; Mice ; Mice, Knockout ; Mitochondria/pathology ; Oxidative Stress ; Retinal Pigment Epithelium/pathology

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 Abca-/- 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.

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P30 EY002162 United States EY NEI NIH HHS; P30 EY016665 United States EY NEI NIH HHS; R01 EY023299 United States EY NEI NIH HHS; R01 EY030668 United States EY NEI NIH HHS

Keywords: Cholesterol; Complement; Ophthalmology; Retinopathy

0 (Apolipoprotein E2)
0 (Apolipoprotein E4)
0 (Ceramides)
0 (Sequestosome-1 Protein)
0 (Sqstm1 protein, mouse)
9007-36-7 (Complement System Proteins)
97C5T2UQ7J (Cholesterol)

Date Created: 20210406 Date Completed: 20220214 Latest Revision: 20220214

20221213

PMC8262309

10.1172/jci.insight.142254

33822768