Biology subjects

Moreno-Santillan, D. D.

Publications and source records attributed to Moreno-Santillan, D. D..

7 recordsLinked to original sources

bioRxiv2026

Iron export and lipid droplets shield deep-diving elephant seal cells from lipid peroxidation

Elephant seals are remarkable breath-hold divers, capable of remaining submerged for up to two hours during diving bouts. These dives entail repeated, extreme hypoxia/reoxygenation events that would induce severe lipid peroxidation and tissue dysfunction in most mammals. Here, we show that primary vascular endothelial cells derived from elephant seals possess an intrinsic resistance to lipid peroxidation. Comparative transcriptomic and lipidomic profiling across seal, human, and sheep cells identified ferroptosis - an iron-dependent, lipid peroxidation-driven cell death pathway - as uniquely regulated in seal cells following hydroperoxide exposure. Mechanistically, seal cells exhibit robust baseline expression of acyl-CoA synthetase long-chain family member 3 (ACSL3), alongside rapid, seal-specific induction of the sole mammalian iron exporter, ferroportin (SLC40A1). Functional validation using genetic and pharmacological approaches revealed that seal cells are naturally enriched in monounsaturated fatty acids and triglycerides and utilize lipid droplet biogenesis and active iron export as dual protective axes to evade lipid peroxidation. Together, these findings show that elephant seal cells employ a coordinated cytoprotective network of lipid remodeling and iron handling to withstand the severe challenges of deep diving. SIGNIFICANCE STATEMENTDeep-diving marine mammals repeatedly experience extreme hypoxia-reoxygenation events that would induce severe oxidative damage in most terrestrial mammals. However, vascular cells derived from seals naturally resist lipid peroxidation, a major driver of ischemia-reperfusion injury. Here, we show that elephant seal endothelial cells evade lipid peroxidation through two complementary mechanisms: lipid droplets that sequester peroxidation-prone phospholipids, and rapid iron export that limits lipid peroxide formation. These findings reveal naturally evolved cellular strategies that protect against vascular oxidative stress, offering new insights into physiological resilience against ischemia-reperfusion injury.

physiology↗

bioRxiv2026

Phthalate exposure induces inflammatory signaling and alters mitochondrial respiration in marine mammal and human cells

This study investigated the transcriptional and bioenergetic responses to monoethylhexyl phthalate (MEHP) in primary fibroblasts derived from northern elephant seals (Mirounga angustirostris), common dolphins (Delphinus delphis), and humans, using RNA-seq, extracellular flux assays, and high-resolution microscopy of the mitochondrial reticulum. MEHP exposure did not induce cytotoxicity but triggered species-specific changes in gene expression and mitochondrial metabolism and morphology. Human cells showed the greatest transcriptional response, upregulating genes involved in detoxification, antioxidant, and inflammation while downregulating lipid metabolism pathways. The highest dose also decreased mitochondrial respiration and increased mitochondrial fragmentation, triggering a metabolic shift toward glycolysis. Elephant seal cells showed delayed glycolytic shifts, maintaining mitochondrial respiration and upregulating antioxidant, immune, and metabolic pathway genes through the highest dose. Despite mitochondrial fragmentation, they upregulated mitochondrial fusion/fission and trafficking genes. Dolphin cells exhibited the fewest changes in gene expression, mostly in hormone signaling and mitotic pathways. They showed dose-dependent declines in both respiration and glycolytic rates, even at the lowest concentration, yet maintained mitochondrial structural integrity while upregulating stress- and hypoxia-induced genes. These distinct strategies highlight species-specific susceptibility to toxicant-induced stress, offering new insights into how marine mammals respond to plastic-derived contaminants and reinforcing the need for species-specific ecotoxicological risk assessments.

physiology↗

bioRxiv2026

Molecular signatures and cellular responses underlying hypoxic adaptation in sea turtles

Hypoxia-inducible factors (HIFs) are transcriptional regulators that orchestrate the canonical response to low-oxygen tension in animal cells. Vertebrates possess three HIF- isoforms, which arose from two gene duplication events of the ancestral HIF-1 gene. Here, we examined whether the HIF gene family (HIF-1, HIF-2, HIF-3, and HIF-1N inhibitor) shows evidence of positive selection in hypoxia-tolerant reptiles (Testudines), compared evolutionary patterns within the family, and assessed the transcriptional response to hypoxia in primary cells derived from a hypoxia-tolerant (Caretta caretta) and a non-tolerant (Sceloporus occidentalis) reptile. We found that HIF-1, HIF-2, and HIF-1N are highly conserved across reptiles, whereas HIF-3 is under positive selection in Testudines. We also identified multiple novel regulatory motifs unique to Testudines. Transcriptional signatures of hypoxia exposure indicated stark differences between lizards and turtles. Whereas lizard cells exhibited a canonical response to hypoxia, characterized by enriched cell-survival pathways, sea turtle cells exhibit a robust, distinctive transcriptional response involving enriched pathways related to protein synthesis, quality maintenance, and mitochondrial integrity. Surprisingly, cis-regulatory element analysis did not show HIFs as key regulators of the transcriptional response in either species. Instead, TFDP1 in lizard cells and E2F1 in sea turtle cells emerged as potential key regulators. TFDP1 regulates the cell cycle, specifically DNA synthesis and cell cycle progression, while E2F regulates DNA-damage response, apoptosis, metabolism, and fatty acid biosynthesis. These results suggest that the reptilian response to hypoxia is shaped by transcriptional plasticity, while highlighting key regulatory mechanisms driving hypoxic adaptation in sea turtle cells. However, positive selection of HIF-3 and novel HIF motifs suggest a combined, but yet to be uncovered, contribution of regulatory and coding sequence evolutionary mechanisms shaping hypoxia tolerance in Testudines.

molecular biology↗

bioRxiv2025

Prolonged fasting and glucocorticoid exposure drive dynamic DNA methylation in elephant seals

Elephant seals experience prolonged fasting while breeding, molting, and undergoing postnatal development. Fasting elephant seals adjust neuroendocrine function and gene expression to cope with potentially detrimental effects associated with extended fasting. DNA methylation alters gene expression by modulating accessibility to regions necessary to initiate transcription. The role of fasting and glucocorticoids on DNA methylation in elephant seals is understudied. We evaluated whether fasting alters global blood DNA methylation, the potential correlation between increased glucocorticoids and methylation, and the effects of glucocorticoids on DNA methylation in seal muscle cells in primary culture. We found that fasting transiently increases blood DNA methylation and that blood DNA methylation levels correlate with plasma cortisol. Hence, we then conducted bioinformatic analyses to identify regions in the elephant seal glucocorticoid receptor (GR) promoter that influence gene transcription through methylation (CPG islands). We identified one CpG island within the putative promoter region of GR gene. Methylation in this region, however, was unaffected by prolonged fasting. We then investigated whether exogenous glucocorticoids alter DNA methylation and gene expression profiles in seal muscle cells in primary culture (myotubes). Exposure to glucocorticoids for 12 or 48 hours decreased DNA methylation while upregulating pro-survival gene expression in seal myotubes. Our results show that whereas prolonged fasting transiently increases DNA methylation in elephant seal blood, sustained exposure to exogenous glucocorticoids decreases DNA methylation and activates a pro-survival transcriptional program in seal myotubes. Therefore, our results suggest that DNA methylation is a plastic, potentially cell-type-specific response that regulates gene expression in fasting seals. Summary statementDNA methylation is a plastic response to fasting and increased glucocorticoids in elephant seals. Our work underscores the role of epigenetic regulation of gene expression during energetically challenging conditions in seals and potentially other mammals.

physiology↗

bioRxiv2023

Hypoxia blunts angiogenic signaling and upregulates the antioxidant system in elephant seal endothelial cells

Elephant seals experience extreme hypoxemia during diving bouts. Similar depletions in oxygen availability characterize pathologies including myocardial infarction and ischemic stroke in humans, but seals manage these repeated episodes without injury. However, the real-time assessment of the molecular changes underlying protection against hypoxic injury in seals remains restricted by their at-sea inaccessibility. Hence, we developed a proliferative arterial endothelial cell culture system to assess the molecular response to prolonged hypoxia. Seal and human cells exposed to 1% O2 for up to 6 h demonstrated differential responses to both acute and prolonged hypoxia. Seal cells decouple stabilization of the hypoxia-sensitive transcriptional regulator HIF-1 from angiogenic signaling at both the transcriptional and cellular level. Rapid upregulation of genes involved in the glutathione (GSH) metabolism pathway supported maintenance of GSH pools and increases in intracellular succinate in seal but not human cells during hypoxia exposure. High maximal and spare respiratory capacity in seal cells after hypoxia exposure occurred in concert with increasing mitochondrial branch length and independent from major changes in extracellular acidification rate, suggesting seal cells recover oxidative metabolism without significant glycolytic dependency after hypoxia exposure. In sum, our studies show that in contrast to human cells, seal cells adapt to hypoxia exposure by dampening angiogenic signaling, increasing antioxidant protection, and maintaining mitochondrial morphological integrity and function.

physiology↗

bioRxiv2023

Chiropterans are a hotspot for horizontal transfer of DNA transposons in Mammalia

Horizontal transfer of transposable elements is an important mechanism contributing to genetic diversity and innovation. Bats (order Chiroptera) have repeatedly been shown to experience horizontal transfer of transposable elements at what appears to be a high rate compared to other mammals. We investigated the occurrence of horizontally transferred DNA transposons involving bats. We found over 200 putative horizontally transferred elements within bats; sixteen transposons were shared across distantly related mammalian clades and two other elements were shared with a fish and two lizard species. Our results indicate that bats are a hotspot for horizontal transfer of DNA transposons. These events broadly coincide with the diversification of several bat clades, supporting the hypothesis that DNA transposon invasions have contributed to genetic diversification of bats.

molecular biology↗

bioRxiv2022

Insights into mammalian TE diversity via the curation of 248 mammalian genome assemblies

We examined transposable element (TE) content of 248 placental mammal genome assemblies, the largest de novo TE curation effort in eukaryotes to date. We find that while mammals resemble one another in total TE content and diversity, they show substantial differences with regard to recent TE accumulation. This includes multiple recent expansion and quiescence events across the mammalian tree. Young TEs, particularly LINEs, drive increases in genome size while DNA transposons are associated with smaller genomes. Mammals tend to accumulate only a few types of TE at any given time, with one TE type dominating. We also found association between dietary habit and the presence of DNA transposon invasions. These detailed annotations will serve as a benchmark for future comparative TE analyses among placental mammals. One-Sentence SummaryA de novo assessment of TE content in 248 mammals finds informative trends in mammalian genome evolution.

genomics↗