Mitochondria in cellular senescence: From mechanistic drivers to therapeutic targets

Mitochondria are increasingly recognized as central regulators of cellular senescence and aging rather than passive bioenergetic organelles. Beyond ATP production, mitochondria coordinate oxidative stress responses, calcium homeostasis, apoptosis, innate immune activation, and metabolic adaptation. Growing evidence indicates that mitochondrial dysfunction is both a driver and a consequence of cellular senescence, creating a self-perpetuating cycle that contributes to chronic inflammation, tissue degeneration, impaired regeneration, and organismal ageing.Senescent cells display profound mitochondrial alterations, including impaired oxidative phosphorylation, excessive production of reactive oxygen species (ROS), disturbed mitochondrial dynamics, defective mitophagy, altered mitochondrial biogenesis, and accumulation of mitochondrial DNA (mtDNA) damage. These changes actively contribute to the maintenance of senescence-associated growth arrest and modulate the Senescence-Associated Secretory Phenotype (SASP), thereby influencing neighbouring cells and tissue microenvironments through paracrine and systemic signaling.Recent studies suggest that mitochondria are not only intracellular regulators of senescence but also important mediators of intercellular communication. Mitochondrial-derived ROS, extracellular mtDNA, mitochondrial transfer, extracellular vesicles, and inflammasome activation have emerged as key mechanisms linking mitochondrial dysfunction to bystander senescence and inflammaging. At the same time, mitochondrial stress responses may have context-dependent protective or adaptive roles, highlighting the complexity of mitochondria–senescence interactions.Despite substantial advances, many critical questions remain unresolved. The precise molecular mechanisms connecting mitochondrial dysfunction to senescence initiation, maintenance, and propagation are incompletely understood. The role of mitochondrial quality control pathways, including mitophagy and mitochondrial unfolded protein responses, requires further clarification. Moreover, therapeutic strategies targeting senescent mitochondria - such as mitochondria-targeted antioxidants, metabolic modulators, mitophagy activators, senolytics, and senomorphics - remain at an early stage of translational development.This Research Topic invites original research and review articles exploring the role of mitochondria in cellular senescence, tissue ageing, and senescence-associated pathologies. We welcome contributions addressing the following areas:• Mitochondrial mechanisms of cellular senescence - mitochondrial ROS, mtDNA damage, oxidative phosphorylation dysfunction, and bioenergetic alterations • Mitochondrial dynamics and quality control - fusion/fission balance, mitophagy, mitochondrial biogenesis, and unfolded protein responses in senescence • Mitochondria and SASP regulation - inflammatory signalling, NF-κB activation, inflammasome pathways, and senescence propagation • Bystander and paracrine senescence mediated by mitochondrial dysfunction, extracellular vesicles, and mtDNA signalling • Mitochondrial dysfunction across ageing tissues and organs - including adipose tissue, cardiovascular system, liver, kidney, immune system, skeletal muscle, and nervous system • Mitochondria and stem cell ageing - effects on regeneration, differentiation, and tissue repair • Immunometabolism and mitochondrial senescence - interactions between mitochondrial dysfunction, immune ageing, and inflammaging • Mitochondria-targeted senolytics and senomorphics - mechanisms of selectivity, efficacy, and therapeutic potential • Biomarkers of mitochondrial senescence - circulating mtDNA, metabolic signatures, imaging approaches, and liquid biopsy strategies • Translational and clinical studies targeting mitochondrial dysfunction and senescence-associated disorders This Research Topic is particularly timely given the growing recognition that mitochondrial dysfunction represents a fundamental hallmark of ageing and a major regulator of senescence biology. Increasing interest in mitochondria-targeted interventions and senescence-modulating therapies further highlights the need to better understand how mitochondrial alterations shape tissue homeostasis, chronic inflammation, and age-related disease progression. Topic editors: Sona Stemberkova Hubackova, Ruben Dagda Source: https://www.frontiersin.org/research-topics/85276/mitochondria-in-cellular-senescence-from-mechanistic-drivers-to-therapeutic-targets