Mitoception Via the Metabokine GDF15 and Human Health

To survive and thrive, living organisms must monitor and regulate cell-level energy supply, demand, and transformation. They do so through a brain-directed interoceptive process we refer to as “metaboception.” Here, we describe a specific metaboceptive signaling cascade mediated by the metabokine/cytokine growth differentiation factor 15 (GDF15), which we name “mitoception.” Mitoception involves an afferent signaling arm initiated by the integrative stress response (ISR), and an efferent signaling arm that simultaneously promotes energy conservation and fuel mobilization. Afferent mitoceptive signaling is mediated by GDF15 released when cells face energy demand in excess of their energy transformation capacity, creating an “energy gap”. Efferent mitoceptive signaling arises when GDF15 receptors in the brainstem receive the signal and initiate psychological experiences including fatigue and anxiety, together with neuroendocrine stress responses. Mitoceptive outputs thus reprioritize systemic energy metabolism to promote allostasis, survival, and long-term health. The proposed GDF15-driven mitoception cascade makes predictions about modifiable processes that shape disease risk, mental health, mood, resilience, well-being, and aging.