Mitochondrial dysfunction activates a translational stress response that drives diabetic pain
Neuropathic pain is common and debilitating among diabetics. The reactive glycolytic metabolite methylglyoxal (MGO) is strongly associated with painful diabetic neuropathy. MGO triggers pain through activation of the integrated stress response (ISR). The underlying molecular mechanisms are unclear. Here, we show that general control nonderepressible 2 (GCN2) kinase acts as a conserved sensor that bridges glycolytic and mitochondrial dysfunction to pain hypersensitivity. In human sensory neurons derived from dorsal root ganglion (DRG), MGO increased eIF2 phosphorylation and suppressed global translation. These effects were blocked upon inhibition of GCN2. Unbiased ribosome profiling of mouse DRG revealed that MGO triggered repression of mRNAs that encode components of the electron transport chain. Based on this observation, mitochondrial dysfunction was examined as a potential upstream trigger for GCN2 activation. MGO directly glycated mitochondrial complex I and increased the NADH/NAD+ ratio. Correcting this redox imbalance via expression of a mitochondrial-targeted bacterial NADH oxidase (mitoLbNOX) prevented ISR activation by MGO. In a streptozotocin-induced mouse model of diabetic neuropathy, pharmacological GCN2 inhibition or sensory neuron-specific conditional deletion significantly attenuated mechanical allodynia. Calcium imaging revealed that genetic deletion of GCN2 reduced calcium influx in response to an agonist of TRPA1. Finally, expression of mitoLbNOX using adeno-associated viruses (AAV) in DRG sensory neurons in vivo reduced streptozotocin-induced mechanical hypersensitivity. Our findings demonstrate that GCN2 is a central, conserved driver of translational dysregulation downstream of mitochondrial redox stress in diabetic pain. This work highlights the critical role of mitochondrial function and translational control as key drivers of painful diabetic neuropathy.