Lipogenesis promotes mitochondrial fusion and maintains cancer stemness in human NSCLC
Zhen Liu, Jiaxin Lei, Tong Wu, Weijie Hu, Ming Zheng, Ying Wang, Jingdong Song, Hang Ruan, Lin Xu, Tao Ren, Wei Xu, Zhenke Wen
Zhen Liu, Jiaxin Lei, Tong Wu, Weijie Hu, Ming Zheng, Ying Wang, Jingdong Song, Hang Ruan, Lin Xu, Tao Ren, Wei Xu, Zhenke Wen
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Research Article Oncology

Lipogenesis promotes mitochondrial fusion and maintains cancer stemness in human NSCLC

Abstract

Cancer stem-like cells (CSCs) are critically involved in cancer metastasis and chemoresistance, acting as one major obstacle in clinical practice. While accumulating studies have implicated the metabolic reprogramming of CSCs, mitochondrial dynamics in such cells remain poorly understood. Here we pinpointed OPA1hi with mitochondrial fusion as a metabolic feature of human lung CSCs, licensing their stem-like properties. Specifically, human lung CSCs exerted enhanced lipogenesis, inducing OPA1 expression via transcription factor SAM Pointed Domain containing ETS transcription Factor (SPDEF). In consequence, OPA1hi promoted mitochondrial fusion and stemness of CSCs. Such lipogenesishi, SPDEFhi, and OPA1hi metabolic adaptions were verified with primary CSCs from lung cancer patients. Accordingly, blocking lipogenesis and mitochondrial fusion efficiently impeded CSC expansion and growth of organoids derived from patients with lung cancer. Together, lipogenesis regulates mitochondrial dynamics via OPA1 for controlling CSCs in human lung cancer.

Authors

Zhen Liu, Jiaxin Lei, Tong Wu, Weijie Hu, Ming Zheng, Ying Wang, Jingdong Song, Hang Ruan, Lin Xu, Tao Ren, Wei Xu, Zhenke Wen

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Figure 1

Higher mitochondrial fusion in CSCs.

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Higher mitochondrial fusion in CSCs. (A) Tumor spheres and adherent cell...
(A) Tumor spheres and adherent cells from A549 were stained with MitoTracker-Red for 15 minutes and detected for mitochondrial dynamics using confocal microscopy. Representative images from 5 independent experiments. Scale bar: 10 μm. (B and C) Tumor spheres and adherent cells from A549 were analyzed for mitochondrial ultrastructural by TEM and quantified for corresponding mitochondrial areas (μm2). Representative and mean ± SEM from 5 independent experiments. Scale bar: 500 nm. (D and E) Mitochondria from A549 tumor spheres or adherent cells were stained with CellLight-Red and MtioTracker-Green at a 1:1 ratio and detected for fusion activity. Representative and mean ± SEM from 8 independent experiments. Scale bar: 5 μm. (F) Oxygen consumption rate (OCR) of A549 tumor sphere and adherent cells. Mean ± SEM from 5 independent experiments. (G) Intracellular ATP levels in A549 tumor sphere and adherent cells. Mean ± SEM from 6 independent experiments. ***P < 0.001 with paired t test. Red arrows point to tubulated and elongated mitochondria. White arrows indicate the mitochondria where fusion occurs.