The co-evolution of mitochondria and the nucleus established constant mito-nuclear communication that is essential for both cellular and organismal homeostasis. At the cell-autonomous level, mitochondrial perturbations activate retrograde pathways such as the mitochondrial unfolded protein response (UPR^mt) and the mitochondrial integrated stress response (ISR^mt), which couple organelle dysfunction to nuclear transcriptional programs, thereby promoting mitochondrial function and preserving cellular integrity. Importantly, this communication is not confined to individual cells but extends across tissues to coordinate systemic adaptations. Stress signals can be sensed, broadcast through secreted mitokines and neural circuits, then interpreted by distal organs to coordinate systemic adaptations. These systemic responses integrate metabolism, immunity, and behavior, conferring resilience to stress and shaping the trajectory of aging. Understanding this multi-layered communication, from the organelle to the organism and its microbial ecosystem, promises new therapeutic strategies to enhance mitochondrial function, promote resilience, and extend healthspan.