PGC-1α-mediated imbalance of mitochondria-lipid droplet homeostasis in neomycin-induced ototoxicity and nephrotoxicity  

作　　者：Bin Chen Cheng Cheng Yunhao Wu Siyu Li Mo Han Le Zhen Ying Peng Suhan Guo Kaidi Shen Xia Gao Renjie Chai Guangji Wang Fang Zhou 

机构地区：[1]Key Laboratory of Drug Metabolism and Pharmacokinetics,State Key Laboratory of Natural Medicines,China Pharmaceutical University,Nanjing 210009,China [2]Department of Otolaryngology Head and Neck Surgery,Nanjing Drum Tower Hospital,Affiliated Hospital of Medical School,Nanjing University,Nanjing 210096,China [3]Co-Innovation Center of Neuroregeneration,Nantong University,Nantong 226001,China [4]Medical Science and Technology Innovation Center,Shandong First Medical University&Shandong Academy of Medical Sciences,Jinan 250117,China [5]State Key Laboratory of Digital Medical Engineering,Department of Otolaryngology Head and Neck Surgery,Zhongda Hospital,School of Life Sciences and Technology,Advanced Institute for Life and Health,Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research,Southeast University,Nanjing 210096,China [6]Department of Neurology,Aerospace Center Hospital,School of Life Science,Beijing Institute of Technology,Beijing 100081,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第10期4413-4430,共18页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(82274014,82330033,82030029,92149304,82101228);the Leading Technology Foundation Research Project of Jiangsu Province(BK20192005,China);National Key R&D Program of China(Nos.2021YFA1101300,2021YFA1101800,and 2020YFA0112503);the Project of State Key Laboratory of Natural Medicines,China Pharmaceutical University(SKLNMZZ202302,China).

摘　　要：Ototoxicity and nephrotoxicity are the most prevalent side effects of aminoglycoside antibiotics(gentamicin,amikacin,neomycin)and platinum anti-tumor drugs(cisplatin,carboplatin).The inner ear and kidney share similarities in drug deposition and toxicity,but the underlying pathophysiological mechanisms remain unclear.Investigating the shared mechanisms and metabolic alterations in these distinct organs will provide valuable insights for clinical therapy.A strong correlation has been identified between the spatiotemporal accumulation patterns of neomycin and the specific occurrence of lipid metabolism disorders in these two organs.The primary allocation of neomycin to mitochondria results in a notable escalation in the accumulation of lipid droplets(LDs)and more interactions between mitochondria and LDs,leading to a sequence of disturbances in lipid metabolism,such as increased lipid ROS and the blocked transfer of fatty acids from LDs to mitochondria.PGC-1αdeficiency worsens the neomycin-induced disorders in lipid metabolism and intensifies the pathological interactions between mitochondria and LDs,as indicated by the exacerbated disturbance of dynamic LD turnover,increased level of oxidized lipids and decreased use of fatty acids.This investigation provides a fresh perspective on the lipid metabolic dysfunction related to mitochondria-LD interactions in drug-induced ototoxicity and nephrotoxicity,potentially providing novel avenues for intervention strategies.

关 键 词：MITOCHONDRIA NEOMYCIN NEPHROTOXICITY OTOTOXICITY Lipid metabolism TRIACYLGLYCEROL PGC-1Α PLIN3 

分 类 号：R91[医药卫生—药学]