Metformin activates the mitochondrial unfolded protein response via the AMPK/SIRT1 pathway to delay intervertebral disc degeneration.

Intervertebral disc degeneration (IDD) is associated with the loss of nucleus pulposus derived mesenchymal stem cell (NP-MSC) function, but the contribution of the mitochondrial unfolded protein response (UPRmt) to this process is not well understood. We found that SIRT1 and the UPRmt-related proteins HSP60, ATF5, and CLPP decreased as degeneration progressed in human disc tissues and primary NP-MSCs. In NP-MSCs exposed to tert-butyl hydroperoxide, metformin increased AMPK phosphorylation and SIRT1 expression, enhanced UPRmt signaling, and reduced apoptosis and senescence. Metformin also improved mitochondrial membrane potential and morphology, lowered reactive oxygen species, restored NAD + levels, and favored extracellular matrix synthesis. Blocking SIRT1 with EX527 or SIRT1 siRNA weakened UPRmt activation and largely reversed the mitochondrial, cellular, and matrix effects of metformin. In a rat needle-puncture model, intradiscal metformin preserved disc height and T2 signal, reduced histological degeneration, and increased matrix and UPRmt-related protein expression; these effects were diminished by EX527. Together, these results suggest that reduced AMPK/SIRT1/UPRmt activity contributes to NP-MSC dysfunction during IDD and that metformin may slow disc degeneration by restoring this mitochondrial stress response.