Mitochondria-dependent phase separation of disease-relevant proteins drives pathological features of age-related macular degeneration
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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 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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Reduced internalization ability of lipApoE2 may protect it against its potentially deleterious structural property.
“its reduced internalization ability may protect it against this potentially deleterious structural property”
From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [73]
The Results section on ApoE trafficking reports that ApoE2 has structural differences associated with impaired intracellular trafficking and cholesterol transport. It does not establish that lipidated ApoE2 has reduced internalization or that reduced internalization protects against those structural effects; intracellular trafficking is not the same as internalization. (LLM, conf=0.76)
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- Authors
- La Cunza, N., Tan, L. X., Thamban, T., Germer, C. J., Rathnasamy, G., Toops, K. A., & Lakkaraju, A.
- Affiliations
- Department of Ophthalmology, School of Medicine, and
- University of California, San Francisco (US)
- University of Wisconsin–Madison (US)
- Corresponding author
- Lakkaraju, Aparna
- ORCID
- Venue
- JCI Insight
- Published
- 2021-05-10
- Volume
- 6
- Issue
- 9
- ISSN
- 2379-3708 (ISSN-L)
- PMC
- PMC8262309
- OpenAlex
- W3142189813
- Cited by
- 65
- References
- 84
- Citations by year
- 2026: 17 · 2025: 11 · 2024: 17 · 2023: 8 · 2022: 10 · 2021: 1 · 2020: 1
- FWCI
- 8.08
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- JCI Insight (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Eye Institute (R01EY023299, R01EY030668, Diversity Supplement Fellowship, P30EY016665, P30EY002162)
- Research to Prevent Blindness/American Macular Degeneration Foundation (Catalyst Award for Innovative Research Approaches to AMD)
- BrightFocus Foundation (M2015350)
- Macular Society UK (AMD research grant)
- Retina Research Foundation (Rebecca Meyer Brown Professorship)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- age-related macular degeneration, retinal pigment epithelium, apolipoprotein E, APOE2, APOE ε4, cholesterol transport, ceramide, autophagy, complement system, mitochondrial damage, liquid-liquid phase separation, biomolecular condensates, p62, drusen, mitochondrial fragmentation, genetic risk variants
- MeSH terms
- Intravital Microscopy, Sequestosome-1 Protein, Biomolecular Condensates, Animals, Autophagy, Ceramides, Cholesterol, Complement System Proteins, Macular Degeneration, Mitochondria, Mice, Knockout, Oxidative Stress, Mice, Apolipoprotein E4, Apolipoprotein E2, Retinal Pigment Epithelium
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