TMBIM-2 orchestrates systemic mitochondrial stress response via facilitating Ca²⁺ oscillations

Neuronal mitochondrial function is critical for orchestrating inter-tissue communication essential for overall fitness. Despite its significance, the molecular mechanism underlying the impact of prolonged mitochondrial stresses on neuronal activity and how they orchestrate metabolism and aging remains elusive. Here, we identified the evolutionarily conserved transmembrane protein XBX-6/TMBIM-2 as a key mediator in the neuronal-to-intestinal mitochondrial unfolded protein response (UPR^mt). Our investigations reveal that intrinsic neuronal mitochondrial stress triggers spatiotemporal Ca²⁺ oscillations in a TMBIM-2-dependent manner through the Ca²⁺ efflux pump MCA-3. Notably, persistent Ca²⁺ oscillations at synapses of ADF neurons are critical for facilitating serotonin release and the subsequent activation of the neuronal-to-intestinal UPR^mt. TMBIM2 expression diminishes with age; however, its overexpression counteracts the age-related decline in aversive learning behavior and extends the lifespan of Caenorhabditis elegans. These findings underscore the intricate integration of chronic neuronal mitochondrial stress into neurotransmission processes via TMBIM-2-dependent Ca²⁺ equilibrium, driving metabolic adaptation and behavioral changes for the regulation of aging.