Biology subjects

Bammidi, S.

Publications and source records attributed to Bammidi, S..

4 recordsLinked to original sources

bioRxiv2026

Gut-derived metabolic reprogramming drives immune aging and tissue degeneration

Aging is characterized by changes in gut microbiome, metabolic imbalance and chronic inflammation, yet how these processes integrate to drive tissue degeneration remains poorly defined. Using age-related macular degeneration (AMD) as a model of tissue aging, we identify a diet-induced metabolic-immune axis that promotes systemic and retinal degeneration. In mice, a high-fat, cholesterol-enriched (HFC) diet induced perturbations in the gut structural integrity and microbiome repertoire, as well as systemic metabolic aging signatures, prominently marked by reduced circulating histidine. Plasma histidine levels were similarly decreased in AMD patients and inversely correlated with body mass index (BMI) in control donors. These diet-induced gut microbiome changes and subsequent metabolic alterations promoted peripheral innate immune reprogramming, with expansion of inflammatory neutrophils and monocytes that infiltrated the outer retina in a mouse model. Mechanistically, the gut-derived IGF1R/AKT2 signaling acts as a central regulator of global epigenetic remodeling and systemic immune aging under high-fat conditions in C. elegans. In a mouse model with an age-dependent dry AMD-like pathology, distinct retinal pigment epithelium (RPE) subpopulations exhibited downregulation of the histidine transporter SLC7A5, linking metabolic stress to activation of MIF/CD74-dependent inflammatory signaling between RPE and infiltrating immune cells. Histidine supplementation or AKT2 phospho-state modulation attenuated systemic immune activation and rescued retinal degeneration. These findings identify histidine-axis dysregulation as a mechanistic bridge between diet-induced microbiome changes, metabolic stress, immune aging, and retinal degeneration.

cell biology↗

bioRxiv2025

A non-canonical AKT1-TERT pathway coordinates autophagy and ERphagy

The retinal pigment epithelium (RPE) sustains lifelong proteostasis under chronic stress, yet how post-mitotic cells activate autophagy when canonical kinase pathways suppress it remains unresolved. Here we demonstrate that AKT1, conventionally regarded as an autophagy suppressor, drives autophagy through a non-canonical transcriptional mechanism triggered by isoform imbalance. In RPE and age-related macular degeneration (AMD) models, AKT2 hyperactivation destabilizes mTORC2 and engages S6K-mediated IRS-1 inhibition, creating a feedforward autophagic arrest. Compensatory AKT1 activation via mTORC2 phosphorylates telomerase reverse transcriptase (TERT) at Serine 824, driving nuclear translocation that is independent of telomere maintenance. In the nucleus, TERT assembles with FOXO3 and MYC into a tripartite transcriptional complex that occupies the EIF2AK3 promoter, enabling PERK transcriptional activation. This activity converts the unfolded protein response from pro-apoptotic to cytoprotective: PERK-ATF4 signaling drives biogenesis of core autophagy machinery while simultaneously inducing selective ERphagy through the receptors TEX264 and CCPG1, which prevents pathological PERK clustering and preserves tubular ER architecture in diseased RPE. Using C. elegans phosphorylation-deficient mutants, mouse models and AMD patient induced pluripotent stem cell-derived retinal pigment epithelium (iPSC-RPE), we establish that AKT1-mediated TERT phosphorylation is an evolutionarily conserved prerequisite for FOXO/DAF-16 nuclear function and lysosomal homeostasis in post-mitotic cells. Pharmacologic targeting of AKT2 with a first-in-class dual-pocket allosteric inhibitor selectively enhances AKT1 compensation, restoring macroautophagic and ERphagy flux across disease models. These findings reveal a kinase-to-transcription axis that reprograms organelle quality control and identify the AKT1-TERT-PERK-ATF4 pathway as a therapeutic target in proteostasis-driven disease.

cell biology↗

bioRxiv2024

βA3/A1-crystallin is an epigenetic regulator of histone deacetylase 3 (HDAC3) in the retinal pigmented epithelial (RPE) cells

Introductory paragraphThe retinal pigmented epithelial (RPE) cells maintain retinal homeostasis, and alterations in their function contribute to non-exudative age-related macular degeneration (AMD)1,2. Here, we explore the intricate relationship between RPE cells, epigenetic modifications, and the development of AMD. Importantly, the study reveals a substantial decrease in histone deacetylase 3 (HDAC3) activity and elevated histone acetylation in the RPE of human AMD donor eyes. To investigate epigenetic mechanisms in AMD development, we used a mouse model with RPE-specific Cryba1 knockout3-5, revealing that the loss of {beta}A3/A1-crystallin selectively reduces HDAC3 activity, resulting in increased histone acetylation. {beta}A3/A1-crystallin activates HDAC3 by facilitating its interaction with the casein kinase II (CK2) and phosphorylating HDAC3, as well as by regulating intracellular InsP6 (phytic acid) levels, required for activating HDAC3. These findings highlight a novel function of {beta}A3/A1-crystallin as an epigenetic regulator of HDAC3 in the RPE cells and provide insights into potential therapeutic strategies in non-exudative AMD.

cell biology↗

bioRxiv2023

The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in atrophic AMD

Introductory paragraphAge-related macular degeneration (AMD), the leading cause of geriatric blindness, is a multi-factorial disease with retinal-pigmented epithelial (RPE) cell dysfunction as a central pathogenic driver. With RPE degeneration, lysosomal function is a core process that is disrupted. Transcription factors EB/E3 (TFEB/E3) tightly control lysosomal function; their disruption can cause aging disorders, such as AMD. Here, we show that induced pluripotent stem cells (iPSC)-derived RPE cells with the complement factor H variant [CFH (Y402H)] have increased AKT2, which impairs TFEB/TFE3 nuclear translocation and lysosomal function. Increased AKT2 can inhibit PGC1, which downregulates SIRT5, an AKT2 binding partner. SIRT5 and AKT2 co-regulate each other, thereby modulating TFEB-dependent lysosomal function in the RPE. Failure of the AKT2/SIRT5/TFEB pathway in the RPE induced abnormalities in the autophagy-lysosome cellular axis by upregulating secretory autophagy, thereby releasing a plethora of factors that likely contribute to drusen formation, a hallmark of AMD. Finally, overexpressing AKT2 in RPE cells in mice led to an AMD-like phenotype. Thus, targeting the AKT2/SIRT5/TFEB pathway could be a potential therapy for atrophic AMD.

cell biology↗