MFN2 deficiency affects calcium homeostasis in lung adenocarcinoma cells via downregulation of UCP4
Jingjing Zhang,
Lifang Pan,
Qiang Zhang,
Yanyan Zhao,
Wenwen Wang,
Nengming Lin,
Shirong Zhang,
Qiong Wu
Affiliations
Jingjing Zhang
Department of Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital Zhejiang Chinese Medical University Hangzhou China
Lifang Pan
Department of Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital Zhejiang Chinese Medical University Hangzhou China
Qiang Zhang
Department of Pharmaceutical and Chemical Engineering Zhengzhou Business Technicians Institute China
Yanyan Zhao
Department of Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital Zhejiang Chinese Medical University Hangzhou China
Wenwen Wang
Department of Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital Zhejiang Chinese Medical University Hangzhou China
Nengming Lin
Department of Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital Zhejiang Chinese Medical University Hangzhou China
Shirong Zhang
Department of Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital Zhejiang Chinese Medical University Hangzhou China
Qiong Wu
Department of Integrated Chinese and Western Medicine The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital) Hangzhou China
Mitofusin‐2 (MFN2) is a transmembrane GTPase that regulates mitochondrial fusion and thereby modulates mitochondrial function. However, the role of MFN2 in lung adenocarcinoma remains controversial. Here, we investigated the effect of MFN2 regulation on mitochondria in lung adenocarcinoma. We found that MFN2 deficiency resulted in decreased UCP4 expression and mitochondrial dysfunction in A549 and H1975 cells. UCP4 overexpression restored ATP and intracellular calcium concentration, but not mtDNA copy number, mitochondrial membrane potential or reactive oxygen species level. Furthermore, mass spectrometry analysis identified 460 overlapping proteins after independent overexpression of MFN2 and UCP4; these proteins were significantly enriched in the cytoskeleton, energy production, and calponin homology (CH) domains. Moreover, the calcium signaling pathway was confirmed to be enriched in KEGG pathway analysis. We also found by protein–protein interaction network analysis that PINK1 may be a key regulator of MFN2‐ and UCP4‐mediated calcium homeostasis. Furthermore, PINK1 increased MFN2/UCP4‐mediated intracellular Ca2+ concentration in A549 and H1975 cells. Finally, we demonstrated that low expression levels of MFN2 and UCP4 in lung adenocarcinoma are associated with poor clinical prognosis. In conclusion, our data suggest not only a potential role of MFN2 and UCP4 in co‐regulating calcium homeostasis in lung adenocarcinoma but also their potential use as therapeutic targets in lung cancer.
