Inhibition of ERK-DLP1 signaling and mitochondrial division alleviates mitochondrial dysfunction in Alzheimer's disease cybrid cell

• Published in: Biochimica et biophysica acta Vol. 1842; no. 2; pp. 220 - 231
• Main Authors: Gan, Xueqi, Huang, Shengbin, Wu, Long, Wang, Yongfu, Hu, Gang, Li, Guangyue, Zhang, Hongju, Yu, Haiyang, Swerdlow, Russell Howard, Chen, John Xi, Yan, Shirley ShiDu
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.02.2014
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Antioxidants - pharmacology; Cybrid cells; DLP1; ERK; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; GTP Phosphohydrolases - genetics; GTP Phosphohydrolases - metabolism; Humans; Hybrid Cells - metabolism; Hybrid Cells - pathology; Immunoblotting; Male; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Middle Aged; Mitochondria - drug effects; Mitochondria - genetics; Mitochondria - metabolism; Mitochondrial Dynamics - drug effects; Mitochondrial Dynamics - genetics; Mitochondrial fission and fusion; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Models, Biological; Mutation; Neurons - metabolism; Neurons - pathology; Probucol - pharmacology; Quinazolinones - pharmacology; Reactive Oxygen Species - metabolism; RNA Interference; Signal Transduction - drug effects; Signal Transduction - genetics; AD; mtDNA; Cybrid cells; DLP1; Mitochondrial fission and fusion; CcO; Aβ; TMRM; PD; ROS; Mfn2; HD; Alzheimer's disease; ERK; Cytochrome c oxidase; Reactive oxygen species; Tetramethylrhodaminemethylester; Huntington disease; Extracellular signal-regulated kinase; Parkinson disease; Mitochondrial DNA; Mitofusin 2; Dynamin-like protein; Amyloid beta peptide
• ISSN: 0925-4439; 0006-3002; 1879-260X
• DOI: 10.1016/j.bbadis.2013.11.009

Mitochondrial dysfunction is an early pathological feature of Alzheimer’s disease (AD). The underlying mechanisms and strategies to repair it remain unclear. Here, we demonstrate for the first time the direct consequences and potential mechanisms of mitochondrial functional defects associated with abnormal mitochondrial dynamics in AD. Using cytoplasmic hybrid (cybrid) neurons with incorporated platelet mitochondria from AD and age-matched non-AD human subjects into mitochondrial DNA (mtDNA)-depleted neuronal cells, we observed that AD cybrid cells had significant changes in morphology and function; such changes associate with altered expression and distribution of dynamin-like protein (DLP1) and mitofusin 2 (Mfn2). Treatment with antioxidant protects against AD mitochondria-induced extracellular signal-regulated kinase (ERK) activation and mitochondrial fission-fusion imbalances. Notably, inhibition of ERK activation not only attenuates aberrant mitochondrial morphology and function but also restores the mitochondrial fission and fusion balance. These effects suggest a role of oxidative stress-mediated ERK signal transduction in modulation of mitochondrial fission and fusion events. Further, blockade of the mitochondrial fission protein DLP1 by a genetic manipulation with a dominant negative DLP1 (DLP1K38A), its expression with siRNA-DLP1, or inhibition of mitochondrial division with mdivi-1 attenuates mitochondrial functional defects observed in AD cybrid cells. Our results provide new insights into mitochondrial dysfunction resulting from changes in the ERK-fission/fusion (DLP1) machinery and signaling pathway. The protective effect of mdivi-1 and inhibition of ERK signaling on maintenance of normal mitochondrial structure and function holds promise as a potential novel therapeutic strategy for AD. •Imbalance of mitochondrial dynamics contributes to AD mitochondrial dysfunction•Activation of ERK/Dlp1 signaling disrupts proper mitochondrial dynamics•Antioxidant and suppressing ERK activation rescue mitochondrial morphology and function•Inhibition of excessive mitochondrial fission protects against AD mitochondrial defects