ASIC1a Induces Excessive Mitophagy and PANoptosis of Chondrocyte by the Inhibition of SIRT3 Mitochondrial Translocation.

Rationale: The death of chondrocytes triggered by extracellular acidification represents a critical factor in the degradation of cartilage tissue and bone, thereby exacerbating the progression of rheumatoid arthritis (RA). Our previous research demonstrated that acid-sensing ion channel 1a (ASIC1a) serves as a key acid sensor mediating the destruction of articular cartilage in RA, which is closely associated with mitochondrial damage of chondrocytes. However, its regulatory mechanism remains unclear. Methods: Cartilage samples from RA patients and collagen-induced arthritis (CIA) rat models were examined to determine the levels of mitophagy and PANoptosis. In parallel, primary rat articular chondrocytes were cultured and subjected to either ASIC1a activation or silencing. Mitochondrial function, mitophagy, and PANoptotic markers were evaluated using immunoblotting, immunofluorescence, and transmission electron microscopy. Additionally, the subcellular distribution of SIRT3 to clarify its role in maintaining mitochondrial homeostasis. Results: We observed a significant increase in the levels of mitophagy and PANoptosis within the cartilage tissue of both RA patients and collagen-induced arthritis (CIA) rat models. Activation of ASIC1a by extracellular acidification triggered mitophagy, ultimately resulting in PANoptosis of chondrocytes. The loss of ASIC1a protected chondrocytes from PANoptosis, thereby alleviating disease progression in CIA rats. Mechanistically, we demonstrated that the transport of SIRT3 from cytoplasm to mitochondria was inhibited upon ASIC1a activation. ASIC1a upregulated calcineurin (CaN) expression, which competitively bound to HSP70, disrupting the SIRT3-HSP70 complex and thereby impairing SIRT3 mitochondrial translocation. The reduced levels of SIRT3 in mitochondria induced mitochondrial dysfunction and excessive mitophagy in primary rat articular chondrocytes, ultimately leading to PANoptosis of chondrocytes. Restoration of SIRT3 improved mitochondrial dysfunction and inhibited excessive mitophagy in the process of ASIC1a-induced PANoptosis of chondrocytes. Conclusion: Our study demonstrated that ASIC1a induces the destruction of articular cartilage through the disruption of the equilibrium between mitochondrial quality control and cell fate. This suggests that ASIC1a is a promising therapeutic target to improve the clinical treatment of RA.