4-methylene-2-octyl-5-oxotetrahydrofuran-3-carboxylic acid (C75), an inhibitor of fatty-acid synthase, suppresses the mitochondrial fatty acid synthesis pathway and impairs mitochondrial function.
4-Methylene-2-octyl-5-oxotetrahydrofuran-3-carboxylic acid (C75) is a synthetic fatty-acid synthase (FASN) inhibitor with potential therapeutic effects in several cancer models. Human mitochondrial β-ketoacyl-acyl carrier protein synthase (HsmtKAS) is a key enzyme in the newly discovered mitochondrial fatty acid synthesis pathway that can produce the substrate for lipoic acid (LA) synthesis. HsmtKAS shares conserved catalytic domains with FASN, which are responsible for binding to C75. In our study, we explored the possible effect of C75 on HsmtKAS and mitochondrial function. C75 treatment decreased LA content, impaired mitochondrial function, increased reactive oxygen species content, and reduced cell viability. HsmtKAS but not FASN knockdown had an effect that was similar to C75 treatment. In addition, an LA supplement efficiently inhibited C75-induced mitochondrial dysfunction and oxidative stress. Overexpression of HsmtKAS showed cellular protection against low dose C75 addition, whereas there was no protective effect upon high dose C75 addition. In summary, the mitochondrial fatty acid synthesis pathway has a vital role in mitochondrial function. Besides FASN, C75 might also inhibit HsmtKAS, thereby reducing LA production, impairing mitochondrial function, and potentially having toxic effects. LA supplements sufficiently ameliorated the toxicity of C75, showing that a combination of C75 and LA may be a reliable cancer treatment.
From the Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology (FIST), Xi'an Jiaotong University, Xi'an 710049, China.
Cong
C
Chen
From the Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology (FIST), Xi'an Jiaotong University, Xi'an 710049, China.
Xiao
X
Han
From the Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology (FIST), Xi'an Jiaotong University, Xi'an 710049, China.
Xuan
X
Zou
From the Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology (FIST), Xi'an Jiaotong University, Xi'an 710049, China.
Yuan
Y
Li
From the Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology (FIST), Xi'an Jiaotong University, Xi'an 710049, China.
Liang
L
Yang
From the Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology (FIST), Xi'an Jiaotong University, Xi'an 710049, China.
Ke
K
Cao
From the Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology (FIST), Xi'an Jiaotong University, Xi'an 710049, China.
Jie
J
Xu
From the Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology (FIST), Xi'an Jiaotong University, Xi'an 710049, China.
Jiangang
J
Long
From the Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology (FIST), Xi'an Jiaotong University, Xi'an 710049, China j.liu@mail.xjtu.edu.cn.
Jiankang
J
Liu
From the Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology (FIST), Xi'an Jiaotong University, Xi'an 710049, China zhfeng@mail.xjtu.edu.cn.
Zhihui
Z
Feng
D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology; D002470:Cell Survival; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D054890:Fatty Acid Synthase, Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D008063:Thioctic Acid / Q000096:biosynthesis*
C406734:4-methylene-2-octyl-5-oxofuran-3-carboxylic acid; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D008063:Thioctic Acid; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I; D015107:4-Butyrolactone
Antioxidant; Fatty-acid Synthase (FAS); Mitochondria; Mitochondrial Disease; Oxidative Stress; Reactive Oxygen Species (ROS)