Poster abstracts
Poster number 17 submitted by Hayley Barta
Glucocorticoids disrupt mitochondrial quality control through metabolic reprogramming in the heart
Hayley Barta (Molecular, Cellular, and Developmental Biology Graduate Program), Nataliia Vasileva (Department of Physiology and Cell Biology, The Ohio State University), Samhita Chaudhuri (Department of Physiology and Cell Biology, The Ohio State University), Kangxuan Chen, Nuo Sun (Department of Physiology and Cell Biology, The Ohio State University)
Abstract:
Symptoms of heart failure (HF) are often worsened by chronic psychological stress. Current therapies alleviate symptoms but fail to address the molecular mechanisms by which stress accelerates HF progression. Central to stress adaptation is the hypothalamus-pituitary-adrenal (HPA) axis, which regulates glucocorticoid (GC) signaling. Dysregulation of this axis causes sustained elevation of stress hormones such as cortisol, and prolonged GC exposure has been linked to cardiovascular complications including hypertension, arrhythmias, and cardiac hypertrophy. Increasing evidence suggests that mitochondria are key mediators of GC-induced cardiac pathology. The heart relies on mitochondrial metabolism to meet its energetic demands, and cardiomyocytes (CMs) contain the highest mitochondrial density of any cell type, making them particularly vulnerable to mitochondrial dysfunction. Maintenance of mitochondrial integrity depends on mitophagy, a selective mitochondrial quality control (MQC) pathway that removes damaged mitochondria. Impaired mitophagy leads to accumulation of dysfunctional mitochondria, a hallmark of HF progression. To investigate how stress signaling disrupts MQC, we used the pH-sensitive mt-Keima reporter in hiPSC-derived CMs to quantify mitophagy under physiological and stress conditions. Cortisol treatment suppressed mitophagy in CMs, particularly under hypoxic stress, where prolonged exposure blunted adaptive responses. Supporting these findings, mice exposed to corticosterone in drinking water exhibited reduced mt-Keima red-to-green ratios in cardiac tissue, indicating suppressed mitophagy in vivo under chronic GC exposure. This suppression was accompanied by accumulation of the autophagy adaptor protein p62 and impaired LC3-I to LC3-II conversion, indicating disrupted autophagic flux. Transcriptomic analysis revealed GC-dependent changes in metabolic pathways, suggesting that stress signaling rewires cellular metabolism alongside impaired MQC. Together, these findings identify a mechanism linking chronic stress signaling to disrupted mitophagy and provide insight into how persistent stress accelerates HF progression, highlighting potential therapeutic targets for stress-induced cardiometabolic dysfunction.
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Keywords: Mitochondria, Glucocorticoids, Metabolism