Mitochondrial Proteostasis: Intersecting Drivers of Cellular Longevity and Vulnerability

Long-lived and highly specialized cells depend on tightly coordinated networks to maintain protein quality control, bioenergetic homeostasis, and genomic integrity across the lifespan. Disruption of these processes, through aberrant cell cycle re-entry, senescence, or failure of mitochondrial proteostasis, represents a fundamental axis of vulnerability in tissue aging, chronic disease, and neurodegeneration.Emerging evidence suggests that cell cycle regulation and mitochondrial quality control, historically studied in isolation, are deeply integrated, converging through shared upstream metabolic stressors and overlapping downstream consequences, including the integrated stress response, metabolic reprogramming, and progressive loss of cellular identity. Defining these points of intersection is essential for understanding how cellular homeostasis destabilizes across tissues and over time, and for translating that insight into disease-relevant contexts. Neurodegeneration, where post-mitotic neurons are acutely sensitive to both aberrant cell cycle re-entry and mitochondrial failure, offers a particularly compelling application, alongside cardiovascular and aging-related pathologies.This Research Topic aims to establish a mechanistically grounded, integrative framework examining how dysregulation of cell cycle control and mitochondrial proteostasis intersect to drive cellular vulnerability or resilience. We welcome original research, reviews, and perspectives using cross-species, multi-model (in vitro, in vivo, in silico) and multidisciplinary approaches addressing:Cell cycle dysregulation and aberrant re-entry — mechanisms of abnormal cell cycle activation and endoreplication in post-mitotic and long-lived cells, and their consequences for genomic stability and survival.Mitochondrial proteostasis and organelle cross-talk — protein folding, disaggregation, and turnover within mitochondria; the UPRmt; and mitochondria–ER–lysosome communication networks.Metabolic and redox signaling to the nucleus — mitochondrial calcium dynamics, redox regulation, and metabolite-driven signals that interface with nuclear stress responses and transcriptional programs.Integrated stress responses and cellular identity — how the ISR, cytosolic UPR, and senescence programs are coordinated, and their contribution to stress adaptation versus loss of specialized cell fate.Shared upstream triggers and feedback loops — common drivers such as chronic inflammation, metabolic stress, and proteotoxicity, and the feedback circuits that link organelle dysfunction back to cell cycle checkpoints.Translational and therapeutic relevance — neurodegeneration (e.g., Alzheimer’s disease) as a central application, alongside cardiovascular and aging-related pathologies, and therapeutic strategies targeting shared molecular nodes. Topic editors: Shyama Nandakumar, Natasha Jaiswal Source: https://www.frontiersin.org/research-topics/82269/mitochondrial-proteostasis-intersecting-drivers-of-cellular-longevity-and-vulnerability