Molecular Dysfunctions of Mitochondria-Associated Membranes (MAMs) in Alzheimer’s Disease

Eysert, Fanny; Kinoshita, Paula Fernanda; Mary, Arnaud; Vaillant-Beuchot, Loan; Checler, Frédéric; Chami, Mounia

doi:10.3390/ijms21249521

Cited by 41 publications

(33 citation statements)

References 235 publications

(200 reference statements)

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“…In controlling the intracellular Ca 2+ concentrations, mitochondria interact with the ER through mitochondria-associated ER membranes (MAMs) [ 73 ], microdomains where the OMM is just 10–100 nanometers apart from the ER [ 74 , 75 ]. These areas are enriched in inositol 1,4,5-triphosphate receptors (IP3Rs) [ 76 ] which form functional complexes with VDACs through a chaperone, Grp75 (glucose-regulated protein 75), belonging to the heat shock protein 70 family [ 77 ].…”

Section: Mitochondria In the Brainmentioning

confidence: 99%

Insights into the Pathogenesis of Neurodegenerative Diseases: Focus on Mitochondrial Dysfunction and Oxidative Stress

Jurcău

2021

IJMS

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As the population ages, the incidence of neurodegenerative diseases is increasing. Due to intensive research, important steps in the elucidation of pathogenetic cascades have been made and significantly implicated mitochondrial dysfunction and oxidative stress. However, the available treatment in Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis is mainly symptomatic, providing minor benefits and, at most, slowing down the progression of the disease. Although in preclinical setting, drugs targeting mitochondrial dysfunction and oxidative stress yielded encouraging results, clinical trials failed or had inconclusive results. It is likely that by the time of clinical diagnosis, the pathogenetic cascades are full-blown and significant numbers of neurons have already degenerated, making it impossible for mitochondria-targeted or antioxidant molecules to stop or reverse the process. Until further research will provide more efficient molecules, a healthy lifestyle, with plenty of dietary antioxidants and avoidance of exogenous oxidants may postpone the onset of neurodegeneration, while familial cases may benefit from genetic testing and aggressive therapy started in the preclinical stage.

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Section: Mitochondria In the Brainmentioning

confidence: 99%

Insights into the Pathogenesis of Neurodegenerative Diseases: Focus on Mitochondrial Dysfunction and Oxidative Stress

Jurcău

2021

IJMS

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“…The ER-mitochondria contacts are also involved in the ER stress-mediated cell death and UPR, because several ER co-factors and chaperones are present at MAM. Moreover, impairment in the UPR, apoptosis, and misfolded proteins accumulation are common features of AD [ 87 ]. In the early phase of ER stress, the cell adapts to stressful conditions through the increase of ER-mitochondria connection, which facilitates mitochondrial Ca 2+ uptake and ATP production.…”

Section: Discussionmentioning

confidence: 99%

Structural and Functional Alterations in Mitochondria-Associated Membranes (MAMs) and in Mitochondria Activate Stress Response Mechanisms in an In Vitro Model of Alzheimer’s Disease

et al. 2021

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Alzheimer’s disease (AD) is characterized by the accumulation of extracellular plaques composed by amyloid-β (Aβ) and intracellular neurofibrillary tangles of hyperphosphorylated tau. AD-related neurodegenerative mechanisms involve early changes of mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) and impairment of cellular events modulated by these subcellular domains. In this study, we characterized the structural and functional alterations at MAM, mitochondria, and ER/microsomes in a mouse neuroblastoma cell line (N2A) overexpressing the human amyloid precursor protein (APP) with the familial Swedish mutation (APPswe). Proteins levels were determined by Western blot, ER-mitochondria contacts were quantified by transmission electron microscopy, and Ca2+ homeostasis and mitochondria function were analyzed using fluorescent probes and Seahorse assays. In this in vitro AD model, we found APP accumulated in MAM and mitochondria, and altered levels of proteins implicated in ER-mitochondria tethering, Ca2+ signaling, mitochondrial dynamics, biogenesis and protein import, as well as in the stress response. Moreover, we observed a decreased number of close ER-mitochondria contacts, activation of the ER unfolded protein response, reduced Ca2+ transfer from ER to mitochondria, and impaired mitochondrial function. Together, these results demonstrate that several subcellular alterations occur in AD-like neuronal cells, which supports that the defective ER-mitochondria crosstalk is an important player in AD physiopathology.

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“…[ 40–44 ] For example, MAMs structure alteration involved in pathophysiological process of Alzheimer's disease, so authors assumed that MAMs should constitute a new therapeutic target in AD. [ 45 ] Another study showed that MAMs disorder participated in hepatic insulin resistance of type 2 diabetic rats. [ 46 ] In our study, DIO improved Ca 2+ homeostasis and MAM structure greatly.…”

Section: Discussionmentioning

confidence: 99%

Diosgenin Protects Against Kidney Injury and Mitochondrial Apoptosis Induced by 3‐MCPD Through the Regulation of ER Stress, Ca²⁺ Homeostasis, and Bcl2 Expression

Zhong

Jin

Han

et al. 2021

Molecular Nutrition Food Res

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Scope Diosgenin (DIO) is a natural steroid sapogenin presented in various plants. It exerts anti‐oxidant, anti‐inflammatory and anti‐diabetic nephropathy properties. The present study evaluates the intervention effect of DIO on nephrotoxicity induced by food contaminant 3‐chloro‐1, 2‐propanediol (3‐MCPD) in vivo and in vitro. Methods and Results Treatment with DIO (15 mg kg−1 d−1) in Sprague‐Dawley rats for 4‐week relieves kidney injury induced by 3‐MCPD (30 mg kg−1 d−1). In vitro, DIO (2, 6, and 8 µM) alleviates cell injury and apoptosis effectively in human embryonic kidney (HEK293) cells. DIO realizes its protective function via the regulation of endoplasmic reticulum (ER) stress and mitochondrial apoptosis pathway. Blockage of ER stress by 4‐phenylbutyric acid (4‐PBA), a specific ER stress antagonist, inhibits mitochondrial apoptosis, suggesting a connection between mitochondrial apoptosis and ER stress. Furthermore, the study demonstrates that the maintenance of Ca2+ homeostasis and Bcl2 expression, two main targets of ER stress, contributes to the protection role of DIO on mitochondrial‐dependent apoptosis. In addition, DIO relieves the impairment of oxidative phosphorylation. Conclusion This study demonstrates that DIO exerts protective effect against kidney injury, mitochondrial dysfunction, and apoptosis through the inhibition of ER stress and the further maintenance of Ca2+ homeostasis and Bcl2 expression.

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Molecular Dysfunctions of Mitochondria-Associated Membranes (MAMs) in Alzheimer’s Disease

Cited by 41 publications

References 235 publications

Insights into the Pathogenesis of Neurodegenerative Diseases: Focus on Mitochondrial Dysfunction and Oxidative Stress

Insights into the Pathogenesis of Neurodegenerative Diseases: Focus on Mitochondrial Dysfunction and Oxidative Stress

Structural and Functional Alterations in Mitochondria-Associated Membranes (MAMs) and in Mitochondria Activate Stress Response Mechanisms in an In Vitro Model of Alzheimer’s Disease

Diosgenin Protects Against Kidney Injury and Mitochondrial Apoptosis Induced by 3‐MCPD Through the Regulation of ER Stress, Ca²⁺ Homeostasis, and Bcl2 Expression

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Molecular Dysfunctions of Mitochondria-Associated Membranes (MAMs) in Alzheimer’s Disease

Cited by 41 publications

References 235 publications

Insights into the Pathogenesis of Neurodegenerative Diseases: Focus on Mitochondrial Dysfunction and Oxidative Stress

Insights into the Pathogenesis of Neurodegenerative Diseases: Focus on Mitochondrial Dysfunction and Oxidative Stress

Structural and Functional Alterations in Mitochondria-Associated Membranes (MAMs) and in Mitochondria Activate Stress Response Mechanisms in an In Vitro Model of Alzheimer’s Disease

Diosgenin Protects Against Kidney Injury and Mitochondrial Apoptosis Induced by 3‐MCPD Through the Regulation of ER Stress, Ca2+ Homeostasis, and Bcl2 Expression

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Diosgenin Protects Against Kidney Injury and Mitochondrial Apoptosis Induced by 3‐MCPD Through the Regulation of ER Stress, Ca²⁺ Homeostasis, and Bcl2 Expression