2. Academic Validation
  3. The role of TBC1D15 in sepsis-induced acute lung injury: Regulation of mitochondrial homeostasis and mitophagy

The role of TBC1D15 in sepsis-induced acute lung injury: Regulation of mitochondrial homeostasis and mitophagy

  • Int J Biol Macromol. 2025 Mar:293:139289. doi: 10.1016/j.ijbiomac.2024.139289.
Hanghang Han 1,  Yingying Zhang 1,  Enhao Huang 1,  Siyu Zhou 1,  Zijin Huang 2,  Ke Qin 3,  Xueke Du 4
Affiliations

Affiliations

  • 1 Department of Anesthesiology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, Guangxi Zhuang Autonomous Region, China; Key Laboratory for Basic Science and Prevention of Perioperative Organ Disfunction, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China.
  • 2 Department of Anesthesiology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, Guangxi Zhuang Autonomous Region, China.
  • 3 Department of Anesthesiology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, Guangxi Zhuang Autonomous Region, China. Electronic address: 202021208@sr.gxmu.edu.cn.
  • 4 Department of Anesthesiology, The Second Affiliated Hospital of Guangxi Medical University, Nanning 530007, Guangxi Zhuang Autonomous Region, China; Key Laboratory for Basic Science and Prevention of Perioperative Organ Disfunction, Guangxi Medical University Cancer Hospital, Nanning 530021, Guangxi Zhuang Autonomous Region, China. Electronic address: GXMUduxueke@outlook.com.
PMID: 39740704 DOI: 10.1016/j.ijbiomac.2024.139289
Abstract

Mitochondrial quality control is crucial in sepsis-induced acute lung injury (SI-ALI). Our study investigates how the intracellular protein TBC1D15 regulates mitochondrial quality to improve SI-ALI. We found TBC1D15 levels significantly decreased in the whole blood of sepsis patients, monocytes, lung tissue from SI-ALI mice, and the MLE-12 cellular model (mouse lung epithelial cells). Overexpression of TBC1D15 using adeno-associated viral and lentiviral vectors alleviated lung injury and inflammation in both mouse models and MLE-12 cells, while silencing TBC1D15 exacerbated inflammatory responses. Mechanistically, TBC1D15 overexpression dissociated mitochondria-lysosome contact duration, promoted Mitophagy, and restored mitochondrial function. The protective effects of TBC1D15 were reversed by the Mitophagy inhibitor Bafilomycin A1. Additionally, TBC1D15 knockdown prolonged mitochondria-lysosome contact time, resulting in worsened mitochondrial dysfunction and increased oxidative stress. Our findings indicate that SI-ALI is characterized by prolonged mitochondria-lysosome contact and impaired Mitophagy. Thus, TBC1D15 overexpression presents a promising therapeutic strategy to mitigate mitochondrial dysfunction and reduce lung injury in septic conditions, suggesting potential clinical applications for SI-ALI treatment.

Keywords

Mitochondrial homeostasis; Sepsis induced acute lung injury; TBC1D15.

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