bims-mideyd 2026-05-24 papers

Cell Death Dis. 2026 May 16.

PIKfyve preserves endolysosomal function in photoreceptors and RPE cells to maintain retinal integrity.

Ammaji Rajala, Larissa J Trevino, Thamaraiselvi Saravanan, Tyler M Black, Mohd A Bhat, Tuan Ngo, Mark Eminhizer, Jianhai Du, Visvanathan Ramamurthy, Raju V S Rajala.

Photoreceptors rely on efficient clearance of outer segment material and mislocalized proteins to maintain cellular health and visual function. While retinal pigment epithelial (RPE) cells remove shed outer segment tips through daily phagocytosis, the mechanisms by which photoreceptors eliminate misfolded or mistargeted proteins are not well understood. Here, we identify PIKfyve, a lipid kinase that synthesizes phosphatidylinositol 3,5-bisphosphate [PI(3,5)P₂], as a key regulator of degradative and metabolic pathways in the retina. PIKfyve is highly expressed in rod photoreceptors, and its selective deletion causes progressive retinal degeneration marked by vacuolation, increased lysosomal markers, loss of outer nuclear layer thickness, and decline of rod and cone function. Partial or complete reduction of PIKfyve further accelerates degeneration in P23H rhodopsin mutant mice. In the RPE, PIKfyve deficiency disrupts phagocytosis and autophagy, leading to the accumulation of rhodopsin, lysosomal proteins, and lipid droplets, accompanied by metabolic imbalance. These results demonstrate that PIKfyve is essential for maintaining photoreceptor and RPE integrity by supporting lysosomal function, protein turnover, and metabolic stability, and suggest that enhancing PIKfyve activity may offer therapeutic potential for retinal degenerative diseases. This study is timely, as pharmacological inhibition of PIKfyve with apilimod-currently under clinical investigation for autoimmune, neurodegenerative, and infectious diseases-raises significant safety concerns, including lysosomal swelling, vacuolization, and impaired protein degradation, which could ultimately compromise retinal homeostasis and vision.

DOI: https://doi.org/10.1038/s41419-026-08855-2

Diabetes. 2026 May 18. pii: db250128. [Epub ahead of print]

cGAS-STING Pathway Mediates Retinal Pigmental Epithelial Dysfunction in Diabetic Retinopathy.

Zhaoqi Zhu, Aowang Qiu, Ningyu Wang, Ziyu Zhu, Wenjie Yin, Ziyun Jiao, Qinghuai Liu, Weiwei Zhang.

Diabetic retinopathy (DR) is a predominant cause of vision impairment among working-age individuals, with a subset of patients responding poorly to current treatments. This study investigated alterations in double-stranded DNA (dsDNA) levels in the aqueous humor and retinal pigment epithelium (RPE) dysfunction in DR patients, exploring the potential role of the cyclic GMP-AMP synthase (cGAS)-STING pathway in DR progression. We found that DR patients showed significantly elevated dsDNA levels in the aqueous humor compared with control individuals. Fundus autofluorescence imaging revealed an increase in high autofluorescence spots in DR patients, indicating early RPE dysfunction. In vivo and in vitro models of DR demonstrated mitochondrial damage and dsDNA leakage in RPE cells, along with cGAS-STING pathway activation in the retina. Pharmacological inhibition of STING reduced cytoplasmic dsDNA accumulation and damaged mitochondria, alleviating inflammation in vitro. In vivo, STING inhibition ameliorated RPE dysfunction and vascular changes. These findings highlight the critical role of the cGAS-STING pathway in DR pathogenesis and suggest that STING inhibition may serve as a promising therapeutic strategy to reduce retinal inflammation and slow the progression of DR.
ARTICLE HIGHLIGHTS: The retinal pigment epithelium (RPE) serves as the outer blood-retinal barrier, protecting the neural retina from systemic changes. We aimed to preserve RPE integrity through early intervention and inhibit DR progression. Our study focused on determining whether the involvement of the cyclic GMP-AMP synthase-STING pathway and mitochondrial damage drive RPE dysfunction. We found that mitochondrial dysfunction in the RPE under diabetic conditions triggers activation of the cyclic GMP-AMP synthase-STING pathway, leading to disruption of RPE and retinal vascular instability. Targeting this pathway restored RPE function and limited retinal deterioration. These findings highlight a promising therapeutic approach for preventing disease progression.

DOI: https://doi.org/10.2337/db25-0128

Mol Neurodegener. 2026 May 16.

Pharmacological restoration of impaired autophagy in retinal ganglion cells prevents abnormal mitochondrial accumulation and glaucomatous neurodegeneration.

Prabhavathi Maddineni, Balasankara Reddy Kaipa, Bindu Kodati, Karthikeyan Kesavan, Linya Li, J Cameron Millar, Sam Yacoub, Ramesh B Kasetti, Abbot F Clark, Gulab S Zode.

BACKGROUND: Progressive loss of retinal ganglion cells (RGCs) and degeneration of optic nerve (ON) axons are the key pathological hallmarks of glaucoma, the leading cause of irreversible blindness. Elevated intraocular pressure (IOP), primarily due to dysfunction of the trabecular meshwork (TM), remains the most significant and only known modifiable risk factor. However, vision loss persists in some patients despite effective IOP control, highlighting the critical need to elucidate the mechanisms driving glaucomatous neurodegeneration. Emerging evidence links mitochondrial dysfunction to glaucomatous neurodegeneration, yet the precise mechanisms remain poorly defined. Here, we investigate whether defective autophagy/mitophagy, which removes damaged mitochondria, contributes to mitochondrial accumulation, oxidative stress, and neurodegeneration in glaucoma. We further explore the therapeutic potential of enhancing autophagy to improve mitochondrial turnover, mitigate RGC loss, and preserve visual function.
METHODS: Glucocorticoid (GC)-induced and myocilin (MYOC)-associated glaucoma mouse models were used to assess the expression of mitochondrial markers (TOM20/COX IV), oxidative DNA damage (8-OHdG), and mitophagy/autophagy-related proteins (p62, LC3, Phospho-ubiquitin (Ser65), and LAMP1) in retinal tissues. Transmission electron microscopy (TEM) was employed to analyze mitochondrial accumulation in glaucomatous ON. Mitophagy flux was assessed at early and late stages of neurodegeneration using mitophagy reporter Mt-Keima mice. The effect of RGC-specific autophagy deficiency on mitochondrial accumulation and neurodegeneration was further investigated using Atg5flox/flox mice, in which Atg5 deletion was induced by AAV2-Cre delivery. Additionally, the therapeutic effect of enhancing autophagy with Torin 2 to restore mitochondrial turnover and prevent glaucomatous neurodegeneration was evaluated in both GC-induced and myocilin-associated glaucoma models, as well as in ex vivo human retinal explants.
RESULTS: Chronic IOP elevation led to increased mitochondrial accumulation, oxidative DNA damage, and impaired mitophagy/autophagy in glaucomatous retina. TEM analysis further confirmed the accumulation of structurally abnormal mitochondria in glaucomatous ON. In Mt-Keima mice, chronic IOP elevation significantly reduced mitophagy flux prior to RGC loss, indicating that mitophagy impairment precedes neurodegeneration. RGC-specific Atg5 deletion induced the accumulation of damaged mitochondria, leading to neurodegeneration in Atg5 flox/flox mice. Notably, pharmacological restoration of impaired autophagy with Torin 2 prevented mitochondrial accumulation and preserved the structural and functional integrity of RGCs and their axons in glaucoma mouse models and ex vivo human retinal explant cultures.
CONCLUSION: Our study indicates impaired autophagy contributes to damaged mitochondrial accumulation and oxidative stress, leading to glaucomatous neurodegeneration. Enhancing autophagy in RGCs represents a promising therapeutic strategy to prevent glaucomatous neurodegeneration.

Keywords: Autophagy; Glaucoma; Intraocular pressure; Mitochondrial dysfunction; Mitophagy; Mouse models of glaucoma; Neurodegeneration; Optic neuropathy; Oxidative DNA damage; Torin 2

DOI: https://doi.org/10.1186/s13024-026-00950-4

J Cell Commun Signal. 2026 Jun;20 e70080

Crosstalk between endoplasmic reticulum stress and mitochondrial homeostasis: A new perspective on ophthalmic disease treatment.

Luyang Jiang, Gongsang Cuomu, Sang Jijia, Yumei Yang, Jufen Liu, Yumin Tao.

Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are hallmarks of many ophthalmic diseases; however, they have traditionally been examined as isolated pathological processes. Recent evidence indicates that these organelles are inextricably coupled through mitochondria-endoplasmic reticulum contact sites, also known as mitochondria-associated membranes (MAMs), which coordinate Ca2+ signaling, lipid transfer, mitochondrial dynamics, redox balance, and cell death decisions. Consequently, dysregulated ER-mitochondria communication has emerged as a key vulnerability that links the cellular stress responses among diverse ocular tissues, including lens epithelial cells, retinal ganglion cells, the retinal pigment epithelium, and corneal endothelial cells. In this review, we summarize the recent advances involving the molecular architecture and regulatory function of ER-mitochondria crosstalk. We focus on how the unfolded protein response signaling, pathological MAM remodeling, Ca2+ dysregulation, and disrupted mitochondrial quality control collectively drive disease progression. By integrating evidence from cataract, glaucoma, diabetic retinopathy, age-related macular degeneration, and Fuchs endothelial corneal dystrophy, we reveal that these disorders are not driven by a uniform mechanism of organelle failure, but rather by the dominance of pathological nodes along the ER-mitochondria axis. We propose that ophthalmic diseases should be stratified based on these distinct failure nodes, which provides a mechanistic framework for developing therapeutics. Within this context, interventions targeting maladaptive ER stress, MAM destabilization, bioenergetic failure, or defective mitophagy should be considered complementary and context-dependent strategies. By reframing ophthalmic disorders as diseases of inter-organelle stress integration, this review positions the ER-mitochondria axis as a modifiable upstream determinant of ocular cell fate, which provides a foundation for stage-specific precision therapies.

Keywords: calcium signaling; endoplasmic reticulum–mitochondria crosstalk; mitochondrial dynamics; mitochondria‐associated membranes; mitophagy; ophthalmic diseases; unfolded protein response

DOI: https://doi.org/10.1002/ccs3.70080

Autophagy. 2026 May 18. 1-20

FASN mediates crosstalk between autophagy and lipid metabolism via the AMPK-MTOR pathway in early age-related macular degeneration.

Jinyu Cai, Yanmei Jiang, Xingyu Liu, Tao Yang, Peizeng Yang, Ling Chen.

Age-related macular degeneration (AMD) involves sub-retinal pigment epithelium (sub-RPE) lipid deposition in the early stage, with dysregulated lipid metabolism and impaired macroautophagy/autophagy implicated, yet the molecular mechanisms underlying their interaction remain unclear. In this study, transcriptomic analysis of human macular tissues identified FASN (fatty acid synthase), a regulator of lipid metabolism and lysosomal function, as a significantly upregulated key hub gene in early AMD. In apoe-/- mice fed a high-fat diet (HFD), retina-RPE-choroid complexes revealed elevated FASN alongside autophagy suppression, lysosomal dysfunction, and lipid accumulation. In vitro, FASN protein levels increased in RPE cells treated with the autophagy inhibitor 3-methyladenine (3-MA), but decreased with the autophagy activator rapamycin (RAPA), without transcriptional changes; lysosomal blockade with chloroquine (CQ) induced FASN accumulation, which was significantly delayed following autophagy inhibition. These findings indicate that FASN accumulation results from insufficient autophagic degradation. Conversely, FASN knockdown or pharmacological inhibition enhanced autophagic flux and promoted lysosomal lipid clearance in RPE cells. Mechanistically, FASN inhibition increased AMPK phosphorylation and decreased MTOR activity, thereby facilitating autophagy and lipophagy. Collectively, our findings reveal a self-amplifying pathological circuit in early AMD: autophagy impairment drives FASN accumulation, which in turn exacerbates lysosomal dysfunction and lipid accumulation. Targeting the FASN-AMPK-MTOR axis may offer a promising therapeutic strategy for early AMD.

Keywords: Age-related macular degeneration; FASN; autophagy; lipid metabolism; lipophagy; retinal pigment epithelium

DOI: https://doi.org/10.1080/15548627.2026.2673559