Abstract

The pain and dysfunction caused by temporomandibular joint osteoarthritis (TMJ OA) can be debilitating. However, effective disease-modifying medicine for TMJ OA remains an unfulfilled need. While progressive cartilage degradation represents the hallmark of TMJ OA, the underlying molecular mechanisms remain incompletely understood. Here, we identify ubiquitin-specific protease 34 (USP34) as a key regulator of mitochondrial quality control in TMJ chondrocytes through its stabilization of adenine nucleotide translocase 1 (ANT1). Using chondrocyte-specific Usp34 KO (Usp34icKO) mice, we first demonstrated age-dependent TMJ OA development characterized by cartilage destruction. Subsequent unilateral bite-raising experiments revealed that USP34 deficiency exacerbated mechanical stress-induced TMJ degeneration. Our results disclosed the dual protective role of USP34 against both age-related and mechanical stress-related TMJ degeneration. Mechanistically, we define the USP34-ANT1 axis as a component upstream of the PINK1-Parkin pathway. USP34 deubiquitinates and stabilizes ANT1, thereby promoting the initiation of Parkin-dependent mitophagy. Additionally, USP34 overexpression confers protection to chondrocytes against cellular injury. These findings establish USP34 as a critical node linking ubiquitin signaling to mitochondrial homeostasis in TMJ chondrocytes and propose targeting USP34 or ANT1 as a potential disease-modifying strategy.