Biology subjects

Pelaez, D.

Publications and source records attributed to Pelaez, D..

6 recordsLinked to original sources

bioRxiv2026

Surface Complex V couples proton gradient across the plasma membrane to ATP production in cancer

Cancer cells alter their metabolism to support growth and survival, most notably by fermenting glucose to lactate even in the presence of oxygen, a phenomenon known as the Warburg effect. Although this metabolic state has been recognized for decades, its bioenergetic advantages remain unclear, as fermentation produces less net ATP than mitochondrial respiration. How aerobic fermentation contributes to cellular energy balance therefore remains unresolved. Here, we show that extracellular acidification generated by lactate export creates a proton gradient across the plasma membrane that is harnessed by ectopic ATP synthases to drive intracellular ATP production. We find that ATP synthase and proton-shuttling components of the mitochondrial respiratory chain translocate to the plasma membrane in cancer cells and are preferentially oriented to exploit this gradient, linking a hallmark of aerobic fermentation directly to energy supplementation. This work provides a mechanistic resolution to the apparent energetic inefficiency of the Warburg paradigm and identifies a previously unrecognized pathway for energy complementation in cancer.

cancer biology↗

bioRxiv2026

Thermoregulatory Constraints on Regenerative Competence: Evolutionary Trade-Offs Between Metabolic Homeostasis and Tissue Repair

Regenerative capacity varies widely across the animal kingdom, yet adult mammals and birds exhibit limited ability to regenerate complex tissues such as the central nervous system (CNS). The evolutionary basis for this loss of regenerative competence remains poorly understood. Here we advance a Thermoregulatory Theory of Regenerative Scope, proposing that the emergence and refinement of endothermic physiology shaped tissue-specific molecular architectures that can bias injury responses away from regeneration in highly metabolic organs. Rather than imposing a systemic energetic constraint, we suggest that endothermy provided the evolutionary context in which thermogenic calcium-handling systems became increasingly specialized in excitable tissues. In particular, futile Ca{superscript 2} cycling across the sarco/endoplasmic reticulum through SERCA pumps contributes to heat generation but may also promote sustained intracellular Ca{superscript 2} elevations that activate inflammatory and fibrotic/gliotic signaling pathways incompatible with functional regeneration. Comparative observations indicate that regenerative competence is retained in ectothermic vertebrates and in mammalian contexts where thermoregulatory systems are developmentally immature or physiologically attenuated. Importantly, regenerative outcomes differ substantially among tissues within endothermic organisms, suggesting that local calcium regulatory architectures, rather than metabolic intensity alone, may determine regenerative potential. This framework generates experimentally testable predictions linking thermogenic Ca{superscript 2} signaling to regenerative failure and provides an evolutionary lens through which disparate observations in regenerative biology may be unified.

evolutionary biology↗

bioRxiv2024

Selective breeding for determinacy and photoperiod sensitivity in common bean (Phaseolus vulgaris L.)

Common bean (Phaseolus vulgaris L.) is a legume pulse crop that provides significant dietary and ecosystem benefits globally. We investigated two key traits, determinacy and photoperiod sensitivity, that are integral to its management and crop production, and that were early selected during the domestication of both Mesoamerican and Andean gene pools. Still, significant variation exists among common bean landraces for these traits. Since landraces form the basis for trait introgression in pre-breeding, understanding these traits genetic underpinnings and relation with population structure is vital for guiding breeding and genetic studies. We explored genetic admixture, principal component, and phylogenetic analyses to define subpopulations and gene pools, and genome-wide association mapping (GWAS) to identify marker-trait associations in a diversity panel of common bean landraces. We observed a clear correlation between these traits, gene pool and subpopulation structure. We found extensive admixture between the Andean and Mesoamerican gene pools in some regions. We identified 13 QTLs for determinacy and 10 QTLs for photoperiod sensitivity, and underlying causative genes. Most QTLs appear to be firstly described. Our study identified known and novel causative genes and a high proportion of pleiotropic effects for these traits in common bean, and likely translatable to other legume species. HighlightWe identified and explored QTLs for the domestication-related determinacy and photoperiod sensitivity traits, which are traits critically associated with population structure and management and crop production.

plant biology↗

bioRxiv2024

Genetic ablation of the DNA demethylation pathway in retinal progenitor cells impairs photoreceptor development and function, leading to retinal dystrophy

Rod and cone photoreceptors are critical for vision, and their loss leads to blindness. Photoreceptors are epigenetically unique, because the promoters of the genes required for the development and function of these neurons are hypermethylated in retinal progenitor cells (RPCs) and hypomethylated in photoreceptors. However, the mechanism responsible for DNA demethylation during the differentiation of RPCs into photoreceptors and its role in photoreceptor development and function were unknown. We hypothesized that the Ten-Eleven Translocation (TET) family of dioxygenases plays a key role in this mechanism. To this end, we knocked out all TET genes in RPCs and characterized the TET-deficient and control retinas using various approaches including electron microscopy, electroretinogram (ERG) tests, RNA-seq, whole genome bisulfite sequencing (WGBS), and 5hmC-Seal. We found that genetic ablation of the TET family prevents demethylation of the promoters of genes essential for rod specification and for rod and cone maturation during the differentiation of RPCs into photoreceptors. Preservation of methylated cytosines in the promoters of these genes significantly reduced their expression, which was confirmed by western blot analysis. This impaired expression leads to the underdevelopment or complete absence of outer segments and synaptic termini in the photoreceptors of TET-deficient retinas, which results in loss of rod and cone function, as assayed by ERG. These function-deprived, underdeveloped photoreceptors die over time, which leads to blindness.

neuroscience↗

bioRxiv2023

Activation of Multiple Eph Receptors on Neuronal Membranes Correlates with The Onset of Traumatic Optic Neuropathy

BackgroundOptic neuropathy (ON) is a major cause of irreversible blindness, yet the molecular determinants that contribute to neuronal demise have not been fully elucidated. Several studies have identified ephrin signaling as one of the most dysregulated pathways in the early pathophysiology of ON with varied etiologies. Developmentally, gradients in ephrin signaling coordinate retinotopic mapping via repulsive modulation of cytoskeletal dynamics in neuronal membranes. Little is known about the role ephrin signaling played in the post-natal visual system and its correlation with the onset of optic neuropathy. MethodsPostnatal mouse retinas were collected for mass spectrometry analysis for Eph receptors. Optic nerve crush (ONC) model was employed to induce optic neuropathy, and proteomic changes during the acute phase of neuropathic onset were analyzed. Confocal and super-resolution microscopy determined the cellular localization of activated Eph receptors after ONC injury. Eph receptor inhibitors assessed the neuroprotective effect of ephrin signaling modulation. ResultsMass spectrometry revealed expression of seven Eph receptors (EphA2, A4, A5, B1, B2, B3, and B6) in postnatal mouse retinal tissue. Immunoblotting analysis indicated a significant increase in phosphorylation of these Eph receptors 48 hours after ONC. Confocal microscopy demonstrated the presence of both subclasses of Eph receptors in the inner retinal layers. STORM super-resolution imaging combined with optimal transport colocalization analysis revealed a significant co-localization of activated Eph receptors with injured neuronal processes, compared to uninjured neuronal and/or injured glial cells, 48 hours post-ONC. Eph receptor inhibitors displayed notable neuroprotective effects after 6 days of ONC injury. ConclusionsOur findings demonstrate the functional presence of diverse Eph receptors in the postnatal mammalian retina, capable of modulating multiple biological processes. Pan-Eph receptor activation contributes to the onset of neuropathy in ONs, with preferential activation of Eph receptors on neuronal processes in the inner retina following optic nerve injury. Notably, Eph receptor activation precedes neuronal loss. We observed neuroprotective effects upon inhibiting Eph receptors. Our study highlights the importance of investigating this repulsive pathway in early optic neuropathies and provides a comprehensive characterization of the receptors present in the developed retina of mice, relevant to both homeostasis and disease processes.

neuroscience↗

bioRxiv2021

RB1 loss triggers dependence on ESRRG in retinoblastoma

Retinoblastoma (Rb) is a deadly childhood eye cancer that is classically initiated by inactivation of the RB1 tumor suppressor. Clinical management continues to rely on nonspecific chemotherapeutic agents that are associated with treatment resistance and toxicity. Here, we analyzed 103 whole exomes, 16 whole transcriptomes, 5 single-cell transcriptomes, and 4 whole genomes from primary Rb tumors to identify novel Rb dependencies. Several recurrent genomic aberrations implicate estrogen-related receptor gamma (ESRRG) in Rb pathogenesis. RB1 directly interacts with and inhibits ESRRG, and RB1 loss uncouples ESRRG from negative regulation. ESRRG regulates genes involved in retinogenesis and oxygen metabolism in Rb cells. ESRRG is preferentially expressed in hypoxic Rb cells in vivo. Depletion or inhibition of ESRRG causes marked Rb cell death which is exacerbated in hypoxia. These findings reveal a novel dependency of Rb cells on ESRRG, and they implicate ESRRG as a potential therapeutic vulnerability in Rb.

cancer biology↗