The cellular basis of mitochondrial stress signaling in the brain

Neuronal vulnerability to stress is highly cell-type specific, but the underlying mechanisms are poorly understood. Here we show that the ability to activate endoplasmic reticulum (ER) stress signaling is encoded by the relative mitochondrial metabolic activity of neurons. Genetically inducing mitochondrial dysfunction in the Drosophila brain caused the emergence of a novel cluster of neurons, detected using single nuclear RNA-sequencing, that activated the ER unfolded protein response (UPR). UPR activation occurred only in neurons with high mitochondrial activity. Unexpectedly, mitochondria-ER contacts were also abundant in the neurons that activated the UPR but virtually undetectable in neurons with low mitochondrial activity. In the human brain, strikingly, excitatory neurogranin neurons had the highest mitochondrial activity and triggered the UPR. The selective activation of the UPR only in neurons with high mitochondrial activity is therefore conserved. This study reveals the remarkable dependence on the inherent oxidative metabolic activity of neurons to activate the UPR.