Mitochondrial calcium uniporter promotes MSU crystal-induced inflammation through inducing mitochondrial Ca²⁺ overload and ubiquitination of SIRT5 protein.

ABSTRACT: The mitochondrial calcium uniporter (MCU) is the key channel regulating mitochondrial calcium (Ca²⁺) uptake. Growing evidence indicates that mitochondrial Ca²⁺ homeostasis plays a pivotal role in regulating immune cell function. However, how MCU contributes to MSU crystal-driven inflammation and its molecular mechanisms are unclear. Using bone marrow-derived macrophages (BMDMs), wild-type (WT, MCU⁺/⁺), and MCU knockout (MCU⁻/⁻) mice, we investigated the role of MCU in MSU crystal-induced inflammation. Co-immunoprecipitation assays were employed to examine interactions among MCU, SIRT5, and TRIM21. MSU crystals stimulation up-regulated MCU expression and triggered mitochondrial Ca²⁺ overload in macrophages. MCU deficiency reduced mitochondrial Ca²⁺ accumulation, ameliorated mitochondrial dysfunction, and suppressed NLRP3 inflammasome activation in BMDMs treated with MSU crystals. Mechanistically, MCU promoted TRIM21 expression, leading to SIRT5 ubiquitination and degradation. Furthermore, MCU facilitated the interaction between TRIM21 and SIRT5, with MSU crystals enhancing this tripartite association. TRIM21 and SIRT5 were identified as key downstream effectors of MCU, mediating MSU crystal-induced inflammatory responses and oxidative stress. In vivo, MCU deficient mice exhibited diminished immune cell infiltration and IL-1β production in MSU crystal-induced peritonitis and arthritis models. Our findings demonstrate that MCU drives mitochondrial Ca²⁺ overload in MSU crystal-induced inflammation and promotes SIRT5 degradation via the TRIM21-SIRT5 signaling axis. These insights highlight MCU as a potential therapeutic target in gouty inflammation.

SUBMITTER: Yu Q 

PROVIDER: S-EPMC12372318 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature