The nervous system is the central hub of the body, detecting environmental and internal stimuli to regulate organismal metabolism via communications to the peripheral tissues. Mitochondria play an essential role in neuronal activity by supplying energy, maintaining cellular metabolism, and buffering calcium levels. A variety of mitochondrial conditions are associated with aging and age-related neurological disorders. Beyond regulating individual neuron cells, mitochondria also coordinate signaling in tissues and organs during stress conditions to mediate systemic metabolism and enable organisms to adapt to such stresses. In addition, peripheral organs and immune cells can also produce signaling molecules to modulate neuronal function. Recent studies have found that mitokines released upon mitochondrial stresses affect metabolism and the physiology of different tissues and organs at a distance. Here, we summarize recent advances in understanding neuron-periphery mitochondrial stress communication and how mitokine signals contribute to the systemic regulation of metabolism and aging with potential implications for therapeutic strategies.