Biology subjects

Gomez, V.

Publications and source records attributed to Gomez, V..

3 recordsLinked to original sources

bioRxiv2025

AKAP1 regulates mitochondrial and synaptic homeostasis to enable neuroprotection and repair in retinal ganglion cell degeneration

Glaucoma is a leading cause of irreversible blindness, characterized by progressive retinal ganglion cell (RGC) loss and optic nerve degeneration. Mitochondrial dysfunction plays a central role in this neurodegeneration, yet effective targeted therapies remain limited. Here, we identify the mitochondrial scaffold A-kinase anchoring protein 1 (AKAP1) as a critical regulator of RGC resilience and axon regeneration. AKAP1 expression is diminished in human glaucomatous retinas and experimental glaucoma models, correlating with elevated intraocular pressure, disrupted mitochondrial dynamics, oxidative stress, and synaptic instability. Restoration of AKAP1 via adeno-associated virus serotype 2-mediated gene therapy preserves RGC survival, promotes mitochondrial fusion and cristae integrity, enhances ATP production, and mitigates oxidative and apoptotic stress in mouse models of glaucoma and optic nerve injury. Transcriptomic profiling of AKAP1 knockout retinas reveals widespread dysregulation of mitochondrial and synaptic gene networks. Mechanistically, AKAP1 stabilizes synapses by promoting mitochondrial biogenesis, modulating calcium/calmodulin-dependent kinase II and synapsin phosphorylation, maintaining synaptophysin expression, and suppressing complement component C1q expression, thereby preventing early synaptic loss in glaucomatous neurodegeneration. Moreover, restoring AKAP1 expression facilitates axonal regeneration, preserves the central visual pathway, and maintains visual function. Collectively, these findings establish AKAP1 as a master regulator of mitochondrial and synaptic homeostasis and axonal regeneration and a promising therapeutic target for vision preservation in glaucomatous neurodegeneration. One Sentence SummaryAKAP1 protects retinal ganglion cells and preserves vision by restoring mitochondrial and synaptic health in experimental glaucoma models.

neuroscience↗

bioRxiv2025

Brucella abortus egresses from host cells in infective clumps through an actin-dependent mechanism

Brucella abortus is an intracellular pathogen whose cell cycle encompasses attachment, internalization, trafficking, replication, and egress from cells. While the intracellular life of Brucella has been extensively studied, the mechanisms underlying its exit from host cells are still unclear. In this work, we observed a significant increase in the formation of B. abortus containing vacuoles intracellular clumps (BCVIC) and abundant B. abortus containing vacuoles-derived extracellular clumps (BCVEC) after 72 h of infection. Membrane extensions protruding through the polymerization of actin filaments were evident in cells at later stages of infection. Purified BCVIC and BCVEC were of similar sizes and predominantly acidic. These vacuoles exhibited a compact arrangement of well-ordered bacteria, comprised of a heterogeneous population of dead and live bacteria and host components LAMP-1 and actin filaments. A proportion of BCVEC were naked, while others were enclosed within an impermeable host membrane. The actin cytoskeleton was implicated in the protrusion of BCVEC since the modulation of Rho GTPases affected the egress of BCVEC. The BCVEC protruding from cells were capable of invading non-infected cells, initiating a new cycle of infection. The topological structure and function of BCVEC underscore their significance in the Brucella life cycle as vehicles for bacterial dissemination to host cells and organs. ImportanceB. abortus is an intracellular pathogen that traffics to the endoplasmic reticulum, where it replicates. However, the mechanisms by which Brucella exits host cells and infects new ones are not fully understood. We found that protruding acidic autophagic-like vesicles containing compact, well-organized Brucella clusters are shed from cells via GTPase and actin filament recruitment. Through this process, the vesicles are impermeable to antibodies and other substances, like antibiotics, and are highly infectious to neighboring cells. This previously unreported mechanism enhances understanding of the well-known Brucella stealth strategy to evade the immune system and establish harmful, long-lasting infections.

microbiology↗

bioRxiv2021

A Budding Yeast Model and Screen to Define the Functional Consequences of Oncogenic Histone Missense Mutations

Somatic missense mutations in histone genes turn these essential proteins into oncohistones, which can drive oncogenesis. Understanding how missense mutations alter histone function is challenging in mammals as mutations occur in a single histone gene. For example, described oncohistone mutations predominantly occur in the histone H3.3 gene, despite the human genome encoding 15 H3 genes. To understand how oncogenic histone missense mutations alter histone function, we leveraged the budding yeast model, which contains only two H3 genes, to explore the functional consequences of oncohistones H3K36M, H3G34W, H3G34L, H3G34R, and H3G34V. Analysis of cells that express each of these variants as the sole copy of H3 reveals that H3K36 mutants show different drug sensitivities compared to H3G34 mutants. This finding suggests that changes to proximal amino acids in the H3 N-terminal tail alter distinct biological pathways. We exploited the caffeine sensitive growth of H3K36 mutant cells to perform a high copy suppressor screen. This screen identified genes linked to histone function and transcriptional regulation, including Esa1, a histone H4/H2A acetyltransferase; Tos4, a forkhead-associated domain-containing gene expression regulator; Pho92, an N6-methyladenosine RNA binding protein and Sgv1/Bur1, a cyclin-dependent kinase. We show that the Esa1 lysine acetyltransferase activity is critical for suppression of the caffeine sensitive growth of H3K36R mutant cells while the previously characterized binding interactions of Tos4 and Pho92 are not required for suppression. This screen identifies pathways that could be altered by oncohistone mutations and highlights the value of yeast genetics to identify pathways altered by such mutations.

genetics↗