The Interaction of Mitochondrial Biogenesis and Fission/Fusion Mediated by PGC-1α Regulates Rotenone-Induced Dopaminergic Neurotoxicity.
Parkinson's disease is a common neurodegenerative disease in the elderly, and mitochondrial defects underlie the pathogenesis of PD. Impairment of mitochondrial homeostasis results in reactive oxygen species formation, which in turn can potentiate the accumulation of dysfunctional mitochondria, forming a vicious cycle in the neuron. Mitochondrial fission/fusion and biogenesis play important roles in maintaining mitochondrial homeostasis. It has been reported that PGC-1α is a powerful transcription factor that is widely involved in the regulation of mitochondrial biogenesis, oxidative stress, and other processes. Therefore, we explored mitochondrial biogenesis, mitochondrial fission/fusion, and especially PGC-1α as the key point in the signaling mechanism of their interaction in rotenone-induced dopamine neurotoxicity. The results showed that mitochondrial number and mass were reduced significantly, accompanied by alterations in proteins known to regulate mitochondrial fission/fusion (MFN2, OPA1, Drp1, and Fis1) and mitochondrial biogenesis (PGC-1α and mtTFA). Further experiments proved that inhibition of mitochondrial fission or promotion of mitochondrial fusion has protective effects in rotenone-induced neurotoxicity and also promotes mitochondrial biogenesis. By establishing cell models of PGC-1α overexpression and reduced expression, we found that PGC-1α can regulate MFN2 and Drp1 protein expression and phosphorylation to influence mitochondrial fission/fusion. In summary, it can be concluded that PGC-1α-mediated cross talk between mitochondrial biogenesis and fission/fusion contributes to rotenone-induced dopaminergic neurodegeneration.
Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, People's Republic of China.
Kaige
K
Peng
Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, People's Republic of China.
Likui
L
Yang
Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, People's Republic of China.
Jian
J
Wang
Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, People's Republic of China.
Feng
F
Ye
Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, People's Republic of China.
Guorong
G
Dan
Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, People's Republic of China.
Yuanpeng
Y
Zhao
Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, People's Republic of China.
Ying
Y
Cai
Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, People's Republic of China.
Zhihong
Z
Cui
Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, People's Republic of China.
Lin
L
Ao
Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, People's Republic of China.
Jinyi
J
Liu
Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, People's Republic of China.
Zhongmin
Z
Zou
Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, People's Republic of China. sai2000cn@163.com.
Yan
Y
Sai
Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, 400038, People's Republic of China. caojia1962@126.com.
Jia
J
Cao
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000235:genetics; D059290:Dopaminergic Neurons / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D063154:Mitochondrial Dynamics / Q000187:drug effects; D009498:Neurotoxins / Q000633:toxicity*; D001678:Organelle Biogenesis; D016716:PC12 Cells; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D012402:Rotenone / Q000633:toxicity*
D004272:DNA, Mitochondrial; D009498:Neurotoxins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D012402:Rotenone
Dopamine neurotoxicity; Mitochondrial biogenesis; Mitochondrial fission/fusion; PGC-1α; Parkinson’s disease; Rotenone