Biology subjects

Korac, K.

Publications and source records attributed to Korac, K..

3 recordsLinked to original sources

bioRxiv2026

Identifying Novel Estrogenic Mitochondrial Targets in Hypothalamic Proopiomelanocortin Neurons by Chemoproteomics

Loss of estrogens at menopause is linked to impaired brain metabolism and increased risk of Alzheimers disease (AD). However, estrogen replacement therapies are limited due to the deleterious effects of estrogen on peripheral organs and increased risk of vascular dementia. We have developed a non-steroidal estrogenic compound, STX, which does not bind to the classical estrogen receptors and {beta}, but mimics estrogenic signaling in the central nervous system (CNS) without the peripheral reproductive actions. STX is protective against neurodegeneration in stroke and AD models, but its molecular targets are unknown. Here, we identified and validated STX neural targets using chemoproteomic, molecular biological, electrophysiological and metabolic assays of hypothalamic proopiomelanocortin (POMC) neurons. Chemoproteomic profiling identified voltage dependent anion channels (VDAC1-3) as major intracellular binding partners in mHypo43 (POMC) cells. Based on quantitative single-cell PCR, Vdac2 was identified as the dominant isoform in female hypothalamic POMC neurons. Seahorse metabolic flux analyses showed that STX potently increased glycolysis, oxidative respiration and mitochondrial ATP production in mHypo43 cells. Nanomolar concentrations of STX enhanced VDAC2 voltage-dependent gating in reconstituted lipid membranes and shifted the low-conductance states toward anion selectivity, consistent with increased ATP flux. Together, these findings reveal a mechanism for the neuroprotective effects of STX through enhancing mitochondrial bioenergetics and modulating VDAC channel properties, potentially increasing cellular energy stores. Therefore, this work identifies previously unrecognized estrogenic mitochondrial targets and provides a mechanistic basis for the neuroprotective actions of STX relevant to menopause-associated brain vulnerability.

neuroscience↗

bioRxiv2026

Single-cell Transcriptomic Variance Analysis Reveals Intercellular Circadian Desynchrony in the Alzheimer's Affected Human Brain

Bulk tissue rhythms arise from the coordination of thousands of individual cellular oscillations. Bulk rhythm amplitude differences may reflect changes in the amplitude of the underlying cellular oscillators or changes in their temporal coherence. To resolve this fundamental ambiguity, we developed ORPHEUS (Oscillatory Rhythm Phase Heterogeneity Estimated Using Statistical-moments), an analytical method that quantifies cellular desynchrony by leveraging the unique 12hr rhythmic signature it imparts on intercellular expression variance. After validating ORPHEUS in silico and on data from the mouse suprachiasmatic nucleus (SCN), we applied it to data from the mouse liver and human brain to uncover disease- and pathway-related differences in intercellular synchrony. In both tissues, we found that circadian synchrony is higher in cells and samples with higher MTORC activity. Most critically, we observed a dramatic loss of cellular synchrony in excitatory neurons from subjects with Alzheimers Disease (AD) dementia. By decoupling the influence of cellular amplitude and synchrony, ORPHEUS introduces a new, interpretable tool for analyzing circadian coordination in time-course single-cell data.

bioinformatics↗

bioRxiv2025

Single-cell RNA sequencing of murine liver reveals an aligned circadian clock and cell-population specific circadian regulated pathways

The circadian clock is tightly connected to metabolism, which is evident in various metabolic processes performed by the liver. Perturbation of these processes due to circadian dysregulation leads to liver specific pathology. The liver is composed of multiple different cell populations each with distinct functions contributing to organ homeostasis, but individual cell population contributions to circadian clock function is not yet known. Single-cell RNA sequencing provides the opportunity to understand clock function and oscillating gene expression within an organ system at the individual cell population level that would allow for better understanding of the crosstalk between the circadian clock and metabolic pathways within the liver. In the past, barriers to achieving this goal included complexity associated with generating single-cell RNA sequencing time series data as well as the complexity of data analysis. Here, we established a protocol that enabled the generation of murine liver cell population time series data, as well as a methodological approach to evaluate the core molecular clock and oscillating gene expression in individual cell populations. Using a combination of normalized coefficient of variation, clock-correlation and aggregate pseudobulk, we found a robust and aligned circadian clock in each of the cell populations. We then employed a pseudoreplicate / pseudobulk strategy to identify oscillating gene expression and benchmarked against bulk RNA sequencing data; we demonstrated that many metabolic genes were oscillating in several of the cell populations, including non-hepatocyte clusters. Finally, we identified oscillating genes unique to specific cell populations that play critical roles in liver function. The findings in this study lay an important foundation for understanding clock function and contributions of oscillating gene function at the individual cell population level in liver.

molecular biology↗