Piezo1 exacerbates inflammation-induced cartilaginous endplate degeneration by activating mitochondrial fission via the Ca2+/CaMKII/Drp1 axis

Mitochondrial homeostasis plays a crucial role in degenerative joint diseases, including cartilaginous endplate (CEP) degeneration. To date, research into mitochondrial dynamics in IVDD is at an early stage. Since Piezo1 is a novel CA²⁺-permeable channel, we asked whether Piezo1 could modulate mitochondrial fission through CA²⁺ signalling during CEP degeneration. In vitro and in vivo models of inflammation-induced CEP degeneration were established with lipopolysaccharide (LPS). We found increased expression of Piezo1 in degenerated CEP tissues and LPS-treated CEP cells. The Piezo1 activator Yoda1 exacerbated CEP cell senescence and Apoptosis by triggering CA²⁺ influx. Yoda1 also induced mitochondrial fragmentation and dysfunction. In contrast, the Piezo1 inhibitor GsMTx4 exerted cytoprotective effects in LPS-treated CEP cells. Additionally, the CaMKII inhibitor KN-93 reversed Yoda1-induced mitochondrial fission and restored mitochondrial function. Mechanistically, the phosphorylation and mitochondrial translocation of Drp1 were regulated by the CA²⁺/CaMKII signalling. The Drp1 inhibitor Mdivi-1 suppressed mitochondrial fission, then reduced mitochondrial dysfunction and CEP cell death. Moreover, knockdown of Piezo1 by siRNA hindered CaMKII and Drp1 activation, facilitating the redistribution of mitochondrial Drp1 to the cytosol in LPS-treated CEP cells. Piezo1 silencing improved mitochondrial morphology and function, thereby rescuing CEP cell senescence and Apoptosis under inflammatory conditions. Finally, subendplate injection of GsMTx4 or AAV-shPiezo1 alleviated CEP degeneration in a rat model. Thus, Piezo1 may exacerbate inflammation-induced CEP degeneration by triggering mitochondrial fission and dysfunction via the CA²⁺/CaMKII/Drp1 axis.

Drp1; Piezo1; apoptosis; cartilaginous endplate degeneration; mitochondrial fission; senescence.