UPR^mt alleviates bone cancer pain through the restoration of mitochondrial function

The mitochondrial unfolded protein response (UPR^mt) is an intracellular retrograde signaling process that facilitates the restoration of mitochondrial homeostasis. Mitochondria are essential for neuronal signaling, and their dysfunction has been implicated as a significant mechanism in the development of chronic pain. Nevertheless, little is known about the exact function of UPR^mt in bone cancer pain (BCP). This research intended to explore the connection between UPR^mt and the progression of BCP. In BCP group, the ultrastructure of spinal cord mitochondria was disrupted, accompanied by a decline in ATP levels and a decrease in Mitochondrial membrane potential (MMP). Concurrently, mRNA and protein levels of UPR^mt marker proteins (Atf5, Hsp60, LonP1, and ClpP) were upregulated, with the expression of Atf5, a key transcription factor of UPR^mt, notably enhanced in spinal dorsal horn neurons. Nicotinamide riboside (NR)-mediated pharmacological augmentation of the UPR^mt significantly alleviated BCP-induced nociceptive hypersensitivity, as demonstrated by elevated mechanical withdrawal thresholds and diminished spontaneous flinching behavior. Concomitant mitochondrial functional recovery was evidenced by restoration of MMP and normalization of ATP level. Notably, genetic knockdown of activating transcription factor 5 (Atf5) abolished both NR-induced UPR^mt activation and the consequent protection against rotenone-mediated mitochondrial dysfunction. These findings establish UPR^mt potentiation as an effective strategy for ameliorating mitochondrial dysfunction and attenuating BCP-associated nociception, proposing this pathway as a novel therapeutic target for clinical pain management.