Mitochondrial UCP4 attenuates MPP+ - and dopamine-induced oxidative stress, mitochondrial depolarization, and ATP deficiency in neurons and is interlinked with UCP2 expression.
Mitochondrial uncoupling proteins (UCPs) uncouple oxidative phosphorylation from ATP synthesis. We explored the neuroprotective role of UCP4 with its stable overexpression in SH-SY5Y cells, after exposure to either MPP(+) or dopamine to induce ATP deficiency and oxidative stress. Cells overexpressing UCP4 proliferated faster in normal cultures and after exposure to MPP(+) and dopamine. Differentiated UCP4-overexpressing cells survived better when exposed to MPP(+) with decreased LDH release. Contrary to the mild uncoupling hypothesis, UCP4 overexpression resulted in increased absolute ATP levels (with ADP/ATP ratios similar to those of controls under normal conditions and ADP supplementation) associated with increased respiration rate. Under MPP(+) toxicity, UCP4 overexpression preserved ATP levels and mitochondrial membrane potential (MMP) and reduced oxidative stress; the preserved ATP level was not due to increased glycolysis. Under MPP(+) toxicity, the induction of UCP2 expression in vector controls was absent in UCP4-overexpressing cells, suggesting that UCP4 may compensate for UCP2 expression. UCP4 function does not seem to adhere to the mild uncoupling hypothesis in its neuroprotective mechanisms under oxidative stress and ATP deficiency. UCP4 overexpression increases cell survival by inducing oxidative phosphorylation, preserving ATP synthesis and MMP, and reducing oxidative stress.
Chu
Andrew Chi-Yuen
AC
Division of Neurology, University Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, People's Republic of China.
Ho
Philip Wing-Lok
PW
Kwok
Ken Hon-Hung
KH
Ho
Jessica Wing-Man
JW
Chan
Koon-Ho
KH
Liu
Hui-Fang
HF
Kung
Michelle Hiu-Wai
MH
Ramsden
David Boyer
DB
Ho
Shu-Leong
SL
D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000276:immunology; D017209:Apoptosis; D002458:Cell Fractionation; D002460:Cell Line; D003001:Cloning, Molecular; D004298:Dopamine / Q000378:metabolism*; D006801:Humans; D007114:Immunization; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000276:immunology; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D026901:Membrane Transport Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D000071245:Mitochondrial Uncoupling Proteins; D009474:Neurons / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D010455:Peptides / Q000008:administration & dosage / Q000138:chemical synthesis; D034741:RNA, Small Interfering; D012756:Sheep; D000071246:Uncoupling Protein 2
D000906:Antibodies; D016056:Immunodominant Epitopes; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D000071245:Mitochondrial Uncoupling Proteins; D010455:Peptides; D034741:RNA, Small Interfering; C117577:SLC25A27 protein, human; C000604389:UCP2 protein, human; D000071246:Uncoupling Protein 2; D000255:Adenosine Triphosphate; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine