Biology subjects

Schwab, E.

Publications and source records attributed to Schwab, E..

3 recordsLinked to original sources

bioRxiv2026

MOTS-c Coordinates Inter-Organellar Proteostasis for Adaptation to Chronic Metabolic Stress

Mitochondrial communication coordinates adaptive responses across organelles to sustain cellular homeostasis, a network that declines with age and contributes to loss of proteostasis. Here, we identify MOTS-c, an exercise-induced mitochondrial-derived peptide (MDP) encoded within the 12S rRNA locus, as an inter-organellar arm of the mitochondrial stress response (MSR) that links mitochondrial signaling to endoplasmic reticulum (ER) proteostasis and enables adaptation to chronic stress. Using progressive stress media (PSM), a model of gradual and multifactorial metabolic stress, we show that MOTS-c enables adaptation through a biphasic program: acutely, a reversible, ATF4-independent suppression of protein synthesis; and chronically, an ATF6-biased ER unfolded protein response (UPRER) with tempered ATF4 engagement and coordinated metabolic remodeling. Whereas mitochondrial unfolded protein response (UPRmt) pathways have been extensively characterized in acute, genetic, and sustained models of mitochondrial perturbation, this work reveals how mitochondrial communication actively engages ER proteostasis during progressive and persistent metabolic stress. By expanding proteostatic capacity while tempering terminal stress signaling, MOTS-c enables cells to withstand chronic stress. Together, these findings define a MOTS-c-dependent arm of the MSR that integrates mitochondrial communication with ER proteostasis to promote chronic metabolic stress adaptation.

Cell Biology↗

bioRxiv2026

Mouse macrophages from diverse niches show generally divergent age-related transcriptional remodeling signatures

BackgroundAging is accompanied by widespread transcriptional remodeling across tissues, yet how aging impacts different categories of tissue-resident macrophages is not well understood. Macrophages are highly specialized innate immune cells shaped by their local microenvironments, suggesting that aging may elicit both shared and niche-specific transcriptional responses. Here, we performed a meta-analysis of publicly available bulk and single cell RNA-sequencing datasets to characterize age-associated transcriptional changes in murine macrophages across tissues and sexes. We curated and uniformly processed 33 macrophage transcriptomic datasets, derived from 10 distinct tissue niches, in male and female C57BL/6 mice, examining transcriptional changes as a function of age. ResultsThe similarity of differentially expressed aging genes was compared across niches and pathway-level analysis uncovered conserved age-associated signatures, including upregulation of gene sets related to antigen presentation, antioxidant responses, and negative regulation of ferroptosis, alongside downregulation of gene sets related to Wnt, GTPase, and extracellular matrix organization signaling. Transcription factor activity inference identified consistent age-associated activation of AP-1 (Fos, Jun), C/EBP{beta}, PU.1, and Egr1 across niches. Meta-analysis defined 593 consistently age-altered genes in >3/4 of analyzed datasets, converging on dysregulation of small GTPase signaling. Focused analysis of alveolar macrophages and microglia, made possible by the larger number of available datasets, revealed sex-specific transcriptional programs altered with age in these macrophage subtypes. ConclusionsThese findings demonstrate that macrophage aging is shaped by both tissue niche and sex and provides a framework for understanding the transcriptomic signatures of macrophage aging across tissues.

genomics↗

bioRxiv2025

Single-cell exploration of ovarian aging across vertebrate models

Mammalian female reproductive span is thought to be limited by a fixed "ovarian reserve" determined at birth. With age, a dwindling ovarian reserve leads to infertility, culminating in menopause in humans. In addition to infertility, accumulating evidence has shown that age-related ovarian functional decline contributes to multisystem aging and frailty, making post-menopausal women most susceptible to an array of chronic diseases. However, due to limited tissue accessibility and lack of reliable research models, molecular drivers of ovarian aging remain poorly understood. A key barrier in the field has been the limited establishment and benchmarking of preclinical models faithfully recapitulating human ovarian biology. To address this, we curated publicly available single-cell/nucleus ovarian RNA-seq datasets from human, macaque, mouse, and goat, and processed them using a consistent and stringent pipeline. Datasets were then annotated in a harmonized fashion across studies in order to conduct a robust, integrative, cross-species analysis of ovarian aging with single cell resolution. We systematically evaluated cell-type composition, global transcriptional perturbations, gene-level changes, pathway and network features, and drug-response alignments. Across analyses, granulosa and theca cells emerged as the cell-types most affected by aging. We observed limited but promising consistencies across species, including granulosa-specific signature genes (FSHR and OSGIN2) and cell type-linked pathways, with extracellular matrix/adhesion programs in granulosa and ribosomal/mitochondrial programs in theca cells. These convergences suggest that cross-species modeling likely capture core aspects of ovarian aging. Together, our meta-analysis approach may help refine model selection, generate testable hypotheses, and cautiously inform preclinical and translational work in ovarian aging.

genomics↗