title: Oxidative stress-mediated activation of extracellular signal-regulated kinase contributes to mild cognitive impairment-related mitochondrial dysfunction.
abstract: Mild cognitive impairment (MCI) occurs during the predementia stage of Alzheimer disease (AD) and is characterized by a decline in cognitive abilities that frequently represents a transition between normal cognition and AD dementia. Its pathogenesis is not well understood. Here, we demonstrate the direct consequences and potential mechanisms of oxidative stress and mitochondrial dynamic and functional defects in MCI-derived mitochondria. Using a cytoplasmic hybrid (cybrid) cell model in which mitochondria from MCI or age-matched non-MCI subjects were incorporated into a human neuronal cell line depleted of endogenous mitochondrial DNA, we evaluated the mitochondrial dynamics and functions, as well as the role of oxidative stress in the resultant cybrid lines. We demonstrated that increased expression levels of mitofusin 2 (Mfn2) are markedly induced by oxidative stress in MCI-derived mitochondria along with aberrant mitochondrial functions. Inhibition of oxidative stress rescues MCI-impaired mitochondrial fusion/fission balance as shown by the suppression of Mfn2 expression, attenuation of abnormal mitochondrial morphology and distribution, and improvement in mitochondrial function. Furthermore, blockade of MCI-related stress-mediated activation of extracellular signal-regulated kinase (ERK) signaling not only attenuates aberrant mitochondrial morphology and function but also restores mitochondrial fission and fusion balance, in particular inhibition of overexpressed Mfn2. Our results provide new insights into the role of the oxidative stress-ERK-Mfn2 signal axis in MCI-related mitochondrial abnormalities, indicating that the MCI phase may be targetable for the development of new therapeutic approaches that improve mitochondrial function in age-related neurodegeneration.
authors: Department of Pharmacology and Toxicology and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA; State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Cheng Du 610041, China.
authors: Xueqi
authors: X
authors: Gan
authors: Department of Pharmacology and Toxicology and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA.
authors: Long
authors: L
authors: Wu
authors: Department of Pharmacology and Toxicology and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA; State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Cheng Du 610041, China.
authors: Shengbin
authors: S
authors: Huang
authors: Department of Pharmacology and Toxicology and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA.
authors: Changjia
authors: C
authors: Zhong
authors: Department of Pharmacology and Toxicology and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA.
authors: Honglian
authors: H
authors: Shi
authors: Department of Pharmacology and Toxicology and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA; State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Cheng Du 610041, China.
authors: Guangyue
authors: G
authors: Li
authors: State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Cheng Du 610041, China.
authors: Haiyang
authors: H
authors: Yu
authors: Department of Neurology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors: Russell
authors: R
authors: Howard Swerdlow
authors: Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors: John
authors: J
authors: Xi Chen
authors: Department of Pharmacology and Toxicology and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA. Electronic address: shidu@ku.edu.
authors: Shirley ShiDu
authors: SS
authors: Yan
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D002478:Cells, Cultured; D003071:Cognition; D060825:Cognitive Dysfunction / Q000235:genetics / Q000473:pathology*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008875:Middle Aged; D008928:Mitochondria / Q000473:pathology; D063154:Mitochondrial Dynamics / Q000235:genetics / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D009474:Neurons; D018384:Oxidative Stress; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction
chemical_list: D005419:Flavonoids; D024101:Mitochondrial Proteins; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D048049:Extracellular Signal-Regulated MAP Kinases; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: Cybrid cells; ERK; Free radicals; Mfn2; Mild cognitive impairment; Mitochondrial fission; Mitochondrial fusion; Oxidative stress