Aβ-Induced Drp1 phosphorylation through Akt activation promotes excessive mitochondrial fission leading to neuronal apoptosis

Kim, Dah Ihm; Lee, Ki Hoon; Gabr, A. A.; Choi, Gee Euhn; Kim, Jun Sung; Ko, So Hee; Han, Ho Jae

doi:10.1016/j.bbamcr.2016.09.003

Cited by 157 publications

(111 citation statements)

References 73 publications

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“…Cytosolic Ca 2+ has been known to play a role in mitochondrial fragmentation in some studies [56], [57]. We found that phosphorylation at the inhibitory site of DRP1 was decreased in ΔMICU1 cells, indicating increased DRP1 activity.…”

Section: Discussionmentioning

confidence: 54%

Pathological consequences of MICU1 mutations on mitochondrial calcium signalling and bioenergetics

Bhosale

Sharpe

Koh

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Loss of function mutations of the protein MICU1, a regulator of mitochondrial Ca2 + uptake, cause a neuronal and muscular disorder characterised by impaired cognition, muscle weakness and an extrapyramidal motor disorder. We have shown previously that MICU1 mutations cause increased resting mitochondrial Ca2+ concentration ([Ca2 +]m). We now explore the functional consequences of MICU1 mutations in patient derived fibroblasts in order to clarify the underlying pathophysiology of this disorder. We propose that deregulation of mitochondrial Ca2+ uptake through loss of MICU1 raises resting [Ca2+]m, initiating a futile Ca2+ cycle, whereby continuous mitochondrial Ca2+ influx is balanced by Ca2+ efflux through the sodium calcium exchanger (NLCXm). Thus, inhibition of NCLXm by CGP-37157 caused rapid mitochondrial Ca2+ accumulation in patient but not control cells. We suggest that increased NCLX activity will increase sodium/proton exchange, potentially undermining oxidative phosphorylation, although this is balanced by dephosphorylation and activation of pyruvate dehydrogenase (PDH) in response to the increased [Ca2+]m. Consistent with this model, while ATP content in patient derived or control fibroblasts was not different, ATP increased significantly in response to CGP-37157 in the patient but not the control cells. In addition, EMRE expression levels were altered in MICU1 patient cells compared to the controls. The MICU1 mutations were associated with mitochondrial fragmentation which we show is related to altered DRP1 phosphorylation. Thus, MICU1 serves as a signal–noise discriminator in mitochondrial calcium signalling, limiting the energetic costs of mitochondrial Ca2+ signalling which may undermine oxidative phosphorylation, especially in tissues with highly dynamic energetic demands. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech.

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Section: Discussionmentioning

confidence: 54%

Pathological consequences of MICU1 mutations on mitochondrial calcium signalling and bioenergetics

Bhosale

Sharpe

Koh

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…Manczak et al found that Drp1 interacts with Aβ monomers and oligomers in AD patients and these abnormal interactions are increased with the disease progression [26]. Dah et al reported Aβ could also activate Drp1 through sustained phosphorylation of Akt [8]. Thus, it is reasonable to suppose that Drp1-Aβ42 interaction is implicated in the regulatory mechanism of Drp1 in Aβ42 transgenic Drosophila .…”

Section: Discussionmentioning

confidence: 99%

“…It was reported that the continuous production, degradation and the aggregation of amyloid beta-protein (Aβ) lead to AD [7]. Aggregation of beta amyloid (Aβ42) and tangles of neuronal fibers are the main pathological features [8,9]. However, the mechanisms driving the disease have not been completely understood.…”

Section: Introductionmentioning

confidence: 99%

Exogenous expression of Drp1 plays neuroprotective roles in the Alzheimer's disease in the Aβ42 transgenic Drosophila model

Yang

Cui

et al. 2017

PLoS ONE

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BackgroundAlzheimer's disease (AD) is one of the most common neurodegenerative disorders. Recent studies have shown that mitochondrial dysfunction is a causative factor of AD. Drp1 (Dynamin-related protein 1), a regulator of mitochondrial fission, shows neuroprotective effects on Parkinson’s disease. In this study, we investigate the effect and mechanism of Drp1 on Aβ42 transgenic Drosophila.MethodsElav-gal4/UAS>Aβ42 transgenic Drosophila model was constructed using Elav-gal4 promoter. The effects of Drp1 on the lifespan, motor ability and neuronal degeneration of the transgenic Drosophila were explored by over-expressing Drp1 in the Aβ42 transgenic Drosophila. ATP levels in the brain tissues of Aβ42 transgenic Drosophila were detected using high performance liquid chromatography (HPLC).ResultsExogenous expression of Drp1 promoted crawling ability, reduced the levels of ATP in Drosophila brain and suppressed the neuronal degeneration.ConclusionThe protective effect of Drp1 on the Aβ42 transgenic Drosophila was achieved by protecting the mitochondrial function, suggesting that Drp1 may be a potential therapeutic strategies for AD.

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“…The second reason is that the decreased clearance of Aβ by some organelles and cellular functions such as the lysosome, proteasome, and autophagy. Hence, drugs which are capable for promoting the clearance or inhibiting the production of Aβ may be a promising therapeutic method toward AD (D. I. Kim et al, ; B. Kim, Park, Chang, & Lee, ; Lv, Yang, Cui, & Su, ; Pickett et al, ; Sarkar, Jun, & Simpkins, ; Yan et al, ).…”

Section: Drp1 and Neurodegenerative Diseasesmentioning

confidence: 99%

Dynamin‐related protein 1: A critical protein in the pathogenesis of neural system dysfunctions and neurodegenerative diseases

Huang

Xie

et al. 2018

Journal Cellular Physiology

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Mitochondria play a key role in the maintenance of neuronal function by continuously providing energy. Here, we will give a detailed review about the recent developments in regards to dynamin‐related protein 1 (Drp1) induced unbalanced mitochondrial dynamics, excessive mitochondrial division, and neuronal injury in neural system dysfunctions and neurodegenerative diseases, including the Drp1 knockout induced mice embryonic death, the dysfunction of the Drp1‐dependent mitochondrial division induced neuronal cell apoptosis and impaired neuronal axonal transportation, the abnormal interaction between Drp1 and amyloid β (Aβ) in Alzheimer's disease (AD), the mutant Huntingtin (Htt) in Huntington's disease (HD), and the Drp1‐associated pathogenesis of other neurodegenerative diseases such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Drp1 is required for mitochondrial division determining the size, shape, distribution, and remodeling as well as maintaining of mitochondrial integrity in mammalian cells. In addition, increasing reports indicate that the Drp1 is involved in some cellular events of neuronal cells causing some neural system dysfunctions and neurodegenerative diseases, including impaired mitochondrial dynamics, apoptosis, and several posttranslational modification induced increased mitochondrial divisions. Recent studies also revealed that the Drp1 can interact with Aβ, phosphorylated τ, and mutant Htt affecting the mitochondrial shape, size, distribution, axonal transportation, and energy production in the AD and HD neuronal cells. These changes can affect the health of mitochondria and the function of synapses causing neuronal injury and eventually leading to the dysfunction of memory, cognitive impairment, resting tremor, posture instability, involuntary movements, and progressive muscle atrophy and paralysis in patients.

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Aβ-Induced Drp1 phosphorylation through Akt activation promotes excessive mitochondrial fission leading to neuronal apoptosis

Cited by 157 publications

References 73 publications

Pathological consequences of MICU1 mutations on mitochondrial calcium signalling and bioenergetics

Pathological consequences of MICU1 mutations on mitochondrial calcium signalling and bioenergetics

Exogenous expression of Drp1 plays neuroprotective roles in the Alzheimer's disease in the Aβ42 transgenic Drosophila model

Dynamin‐related protein 1: A critical protein in the pathogenesis of neural system dysfunctions and neurodegenerative diseases

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