Mitochondrial citrate accumulation triggers senescence of alveolar epithelial cells contributing to pulmonary fibrosis in mice
Jie-Ru Hong,
Ling Jin,
Chen-Yu Zhang,
Wen-Jing Zhong,
Hui-Hui Yang,
Guan-Ming Wang,
Sheng-Chao Ma,
Cha-Xiang Guan,
Qing Li,
Yong Zhou
Affiliations
Jie-Ru Hong
Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China
Ling Jin
Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China
Chen-Yu Zhang
Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China
Wen-Jing Zhong
Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China
Hui-Hui Yang
Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China
Guan-Ming Wang
Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China
Sheng-Chao Ma
NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, Yinchuan 750004, China; The School of Basic Medical Sciences, Ningxia Medical University Yinchuan 750004, China
Cha-Xiang Guan
Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China
Qing Li
Department of Physiology, Hunan University of Medicine, Huaihua, Hunan 418000, China; Corresponding author. Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China,
Yong Zhou
Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410078, China; Corresponding author.
Alveolar epithelial cell (AEC) senescence is implicated in the pathogenesis of pulmonary fibrosis (PF). However, the exact mechanism underlying AEC senescence during PF remains poorly understood. Here, we reported an unrecognized mechanism for AEC senescence during PF. We found that, in bleomycin (BLM)-induced PF mice, the expressions of isocitrate dehydrogenase 3α (Idh3α) and citrate carrier (CIC) were significantly down-regulated in the lungs, which could result in mitochondria citrate (citratemt) accumulation in our previous study. Notably, the down-regulation of Idh3α and CIC was related to senescence. The mice with AECs-specific Idh3α and CIC deficiency by adenoviral vector exhibited spontaneous PF and senescence in the lungs. In vitro, co-inhibition of Idh3α and CIC with shRNA or inhibitors triggered the senescence of AECs, indicating that accumulated citratemt triggers AEC senescence. Mechanistically, citratemt accumulation impaired the mitochondrial biogenesis of AECs. In addition, the senescence-associated secretory phenotype from senescent AECs induced by citratemt accumulation activated the proliferation and transdifferentiation of NIH3T3 fibroblasts into myofibroblasts. In conclusion, we show that citratemt accumulation would be a novel target for protection against PF that involves senescence.
