Uncovering mitochondrial defects in photoreceptors opens therapeutic opportunities for Stargardt disease

mice and STGD1 patient-derived retinal organoids. Specifically, we found reduced mitochondrial content, defective cristae morphology, and downregulation of OPA1, a critical regulator of mitochondrial integrity, demonstrating that photoreceptor defects in STGD1 also have a cell-autonomous origin, besides the RPE dysfunction. Importantly, we also demonstrated that correcting this pathological phenotype through the modulation of microRNAs 181a and b (miR-181a/b), key regulators of mitochondrial function, ameliorates the STGD1 phenotype. Indeed, genetic inactivation and adeno-associated viral vector-mediated silencing of miR-181a/b in STGD1 models restored OPA1 levels, improved mitochondrial phenotype, and reduced lipofuscin accumulation in the RPE. Our study demonstrates that mitochondrial dysfunction in photoreceptors is an important contributor to STGD1 pathology, opening promising therapeutic avenues for this disorder.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2026-04-15
DOI
https://doi.org/10.1073/pnas.2504764123
Primary Topic
Retinal Development and Disorders
Type
article
Field-Weighted Citation Impact
0.00

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article

Uncovering mitochondrial defects in photoreceptors opens therapeutic opportunities for Stargardt disease

Giancarlo Parenti, Carla Damiano, Mariagrazia Volpe, Simona Brillante et al.
Proceedings of the National Academy of Sciences
Retinal Development and Disorders
article

Uncovering mitochondrial defects in photoreceptors opens therapeutic opportunities for Stargardt disease

Giancarlo Parenti, Carla Damiano, Mariagrazia Volpe, Simona Brillante, Erika Tenderini, Antonietta Tarallo, Sandro Banfi, Santiago Negueruela, Anna Diana, Sabrina Carrella, Patrizia Tornabene, Marta Molinari, Alessia Indrieri, Ivana Trapani, Roman Polishchuk, Eva Cipollaro, Elena Polishchuk, Rosa Saurino
article en

Abstract

mice and STGD1 patient-derived retinal organoids. Specifically, we found reduced mitochondrial content, defective cristae morphology, and downregulation of OPA1, a critical regulator of mitochondrial integrity, demonstrating that photoreceptor defects in STGD1 also have a cell-autonomous origin, besides the RPE dysfunction. Importantly, we also demonstrated that correcting this pathological phenotype through the modulation of microRNAs 181a and b (miR-181a/b), key regulators of mitochondrial function, ameliorates the STGD1 phenotype. Indeed, genetic inactivation and adeno-associated viral vector-mediated silencing of miR-181a/b in STGD1 models restored OPA1 levels, improved mitochondrial phenotype, and reduced lipofuscin accumulation in the RPE. Our study demonstrates that mitochondrial dysfunction in photoreceptors is an important contributor to STGD1 pathology, opening promising therapeutic avenues for this disorder.

Proceedings of the National Academy of SciencesVol. 123(16)
National Academies of Sciences, Engineering, and Medicine (US), Stazione Zoologica Anton Dohrn (IT), European School of Molecular Medicine (IT), Santobono Children's Hospital (IT), University of Campania "Luigi Vanvitelli" (IT), University of Naples Federico II (IT)
BrightFocus Foundation, Fondazione Telethon, Ministero dell'Università e della Ricerca
Openalex Percentile: Top 19%
Retinal Development and Disorders
DOIOpen Access PDFOpenAlex
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