Metabolic stress driven by mitochondrial dysfunction underlies a wide range of human diseases, yet the same defect can be detrimental to some cells while sparing their neighbors. We argue that this paradox reflects lineage mosaicism. Tissues are built from diverse clonal lineages whose differences remain hidden until mitochondrial dysfunction unmasks them. Rather than failing uniformly, cells diverge, engaging distinct stress programs shaped by developmental history and local context. By applying lineage-resolved approaches to mitochondrial dysfunction, we can move beyond average cellular behavior to understand when, where, and why individual cells adapt, persist, or fail.

Regular aerobic exercise is associated with increased survival for patients suffering from solid tumor cancers. In the last decade, pre-clinical exercise oncology studies have begun to explore the mechanisms governing the protective effects of exercise, leading to translation of exercise-based regimens into the clinic. However, many patients with intractable solid tumors or those diagnosed at late stage may be physically unable to partake in exercise-based regimens. In this perspective piece, authors argue that the value of pre-clinical exercise oncology work is not limited to direct translation, but should instead be reframed as a means of discovery for novel anti-tumor mechanisms. Exercise-based pre-clinical work should be considered as a discovery engine, wherein mechanisms identified at the intersection of exercise physiology and tumor biology should be independently evaluated for their clinical potential, independent of the need for exercise.

Extracellular vesicles (EVs) are membrane-enclosed particles released by cells carrying proteins, lipids, metabolites and nucleic acids that can alter the behavior of recipient cells. In mammalian systems, EVs have been studied extensively as important mediators of intercellular and interorgan communication in development, tissue homeostasis, immunity, regeneration, metabolism, cancer and neurobiology. In parallel, Drosophila has emerged as a powerful in vivo model for EV research owing to its genetic tractability and the availability of well-established tools for studying interorgan communication. Work in Drosophila has shown that EVs participate in synaptic cargo transfer, developmental and reproductive signaling, neuronal homeostasis and systemic immune responses. Importantly, most of the pathways that regulate endosomal sorting, multivesicular body dynamics, membrane budding and vesicle secretion are conserved between flies and mammals. This review summarizes current understanding of EV nomenclature, biogenesis, cargo selection and biological function, with emphasis on points of convergence and divergence between mammalian and Drosophila systems. It further discusses the strengths and limitations of Drosophila as a model for mammalian EV biology and highlights how comparative approaches can sharpen mechanistic insight and translational EV studies.