Peroxisome dysfunction alters metabolism of photoreceptor outer segments in human retinal pigment epithelium
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Abstract
Peroxisomes are ubiquitous organelles that compartmentalize metabolic reactions including lipid catabolism and cellular detoxification. Pathogenic variants in PEX1 and PEX6 disrupt essential peroxisome functions and cause profound neurodegenerative diseases called peroxisome biogenesis disorders (PBDs). Despite retinal degeneration and blindness occurring frequently in PBDs, precisely how impaired peroxisome activity disrupts retinal function remains to be fully explored. To address this, we differentiated PEX1 -/- , PEX6 -/- , and wildtype human induced pluripotent stem cells into retinal pigment epithelium (iRPE) to study the consequences of peroxisome dysfunction in this disease-relevant cell type. Despite exhibiting impaired peroxisome matrix protein import, PEX1 -/- and PEX6 -/- iRPE had comparable morphology, tight junctions, and expression of proteins characteristic of RPE compared to wildtype iRPE. Targeted lipid profiling revealed reduced docosahexaenoic acid, a polyunsaturated fatty acid (PUFA) essential for retinal function, and elevated lipid species exclusively metabolized by peroxisomes in PEX1 -/- and PEX6 -/- iRPE. Following a photoreceptor outer segment (POS) challenge, PEX1 -/- and PEX6 -/- iRPE demonstrated disrupted PUFA retroconversion and lipid droplet accumulation. Additionally, PEX1 -/- and PEX6 -/- iRPE had impaired rhodopsin degradation, lysosomal dysfunction, and reduced transepithelial electrical resistance. These findings suggest that dysregulated POS metabolism in the RPE is a potential mechanism driving retinal degeneration in patients with PBDs. Graphical abstract Schematic summarizing the consequences of PEX1 and PEX6 knockout on iRPE biology, including the presence of import-incompetent peroxisomes, impaired ω3 and ω6 fatty acid retroconversion, lipid droplet accumulation, and defective photoreceptor outer segment phagocytosis.
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Abstract
Peroxisomes are ubiquitous organelles that compartmentalize metabolic reactions including lipid catabolism and cellular detoxification. Pathogenic variants in PEX1 and PEX6 disrupt essential peroxisome functions and cause profound neurodegenerative diseases called peroxisome biogenesis disorders (PBDs). Despite retinal degeneration and blindness occurring frequently in PBDs, precisely how impaired peroxisome activity disrupts retinal function remains to be fully explored. To address this, we differentiated PEX1-/-, PEX6-/-, and wildtype human induced pluripotent stem cells into retinal pigment epithelium (iRPE) to study the consequences of peroxisome dysfunction in this disease-relevant cell type. Despite exhibiting impaired peroxisome matrix protein import, PEX1-/- and PEX6-/-iRPE had comparable morphology, tight junctions, and expression of proteins characteristic of RPE compared to wildtype iRPE. Targeted lipid profiling revealed reduced docosahexaenoic acid, a polyunsaturated fatty acid (PUFA) essential for retinal function, and elevated lipid species exclusively metabolized by peroxisomes in PEX1-/- and PEX6-/- iRPE. Following a photoreceptor outer segment (POS) challenge, PEX1-/- and PEX6-/- iRPE demonstrated disrupted PUFA retroconversion and lipid droplet accumulation. Additionally, PEX1-/- and PEX6-/-iRPE had impaired rhodopsin degradation, lysosomal dysfunction, and reduced transepithelial electrical resistance. These findings suggest that dysregulated POS metabolism in the RPE is a potential mechanism driving retinal degeneration in patients with PBDs.
Graphical abstractSchematic summarizing the consequences of PEX1 and PEX6 knockout on iRPE biology, including the presence of import-incompetent peroxisomes, impaired ω3 and ω6 fatty acid retroconversion, lipid droplet accumulation, and defective photoreceptor outer segment phagocytosis.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Declaration of Interests: The authors have declared that no conflicts of interest exist.
Figure 7 was updated to include additional data: panels D, E, F, G, and H.
- List of Abbreviations
- AAA
- ATPases Associated with Diverse Cellular Activities
- ACAA1
- Acetyl-Coenzyme A Acyltransferase 1
- ACOX1
- Acyl-Coenzyme A Oxidase 1 BCFAs Branched-Chain Fatty Acids
- DPBS
- Dulbecco’s Phosphate Buffered Saline
- FAs
- Fatty Acids
- iPSCs
- Induced Pluripotent Stem Cells
- iRPE
- iPSC-Derived RPE
- IRDs
- Inherited Retinal Dystrophies
- LDs
- Lipid Droplets
- MFP2
- Multifunctional Protein 2
- PBDs
- Peroxisome Biogenesis Disorders
- POS
- Photoreceptor Outer Segments
- PTS1
- Peroxisomal Targeting Signal-1
- PTS2
- Peroxisomal Targeting Signal-2
- PUFA
- Polyunsaturated Fatty Acids
- RPE
- Retinal Pigment Epithelium
- RPE-MM
- Retinal Pigment Epithelium Maturation Media
- VLCFAs
- Very Long-Chain Fatty Acids
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- last seen: 2026-05-20T01:45:00.602351+00:00
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