Sensing within: Mitochondrial inside-out signal transduction

The prevailing theory on the origins of mitochondria proposes that they were once independent organisms. Though symbiotically integrated into eukaryotic cells, they have retained a striking degree of autonomy. This self-governance manifests as the capacity to sense internal metabolic, ionic, and redox states and transduce these into signals that modulate cellular function—a process we refer to as mitochondrial inside-out signaling. These mitochondria-initiated signaling mechanisms are crucial for bioenergetic homeostasis of all cells, including neurons. Unlike conventional outside-in signaling, these mitochondria-initiated signals stem from within the organelle and propagate outward, tuning cytosolic signaling pathways, nuclear transcriptional programs, and neuronal behavior. In this review, we provide mechanistic insights into this distinct and underappreciated signaling modality, discussing how internal mitochondrial conditions are sensed and transmitted to the cytosol and how these signaling events influence mitochondrial and cellular health with a focus on their implications for neuronal physiology and disease vulnerability.