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. Metabolic energy is monitored through a set of brain-directed interoceptive processes we refer to as metaboception. Here, we review evidence for a specific metaboceptive signaling cascade mediated by the cytokine/metabokine growth differentiation factor 15 (GDF15), which we refer to as mitoception. Mitoception involves an afferent signaling arm initiated by the integrative stress response within cells, and an efferent signaling arm that simultaneously promotes systemic 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. The efferent arm of 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 efficient allostasis, survival, and long-term health. This article is an introduction to GDF15 psychobiology. We propose a GDF15-driven mitoception cascade that makes predictions about modifiable processes shaping fatigue and mood, mental health disorders, the healing process, well-being, and the rate of aging.