Adaptation of mitochondrial network dynamics and velocity of mitochondrial movement to chronic stress present in fibroblasts derived from patients with sporadic form of Alzheimer’s disease

Drabik, Karolina; Piecyk, Karolina; Wolny, Artur; Szulc-Dąbrowska, Lidia; Dębska–Vielhaber, Grażyna; Vielhaber, Stefan; Duszyński, Jerzy; Malińska, Dominika; Szczepanowska, Joanna

doi:10.1096/fj.202001978rr

Cited by 6 publications

(6 citation statements)

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“…This may be a hallmark of a decrease in the cellular metabolic rate accompanying the disease process. Despite that, we did not observe any symptoms of increased cell death in the sAD fibroblasts, their cell morphology was maintained, and only their slower proliferation rates could be a hallmark of the decreased metabolic activity of sAD cells [55]. However, it should be noted that fibroblasts adapt to bioenergetic deficits much more readily than neurons, for which such a degree of mitochondrial disturbances can lead to more severe cellular dysfunction.…”

Section: Discussioncontrasting

confidence: 55%

“…In sAD fibroblasts, the age of the mitochondria did not differ between the perinuclear and distal parts of the cell, which shows that not only the mitophagic clearance of old mitochondria, but also the mechanisms of mitochondrial transport within the cell are defective. Indeed, in our previous work we detected decreased mitochondrial transport velocity, a lower frequency of fusion-fission events and a more fused mitochondrial network in sAD fibroblasts [55]. All of these events can contribute to impairments in mitochondrial turnover.…”

Section: Discussionmentioning

confidence: 69%

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Effect of Chronic Stress Present in Fibroblasts Derived from Patients with a Sporadic Form of AD on Mitochondrial Function and Mitochondrial Turnover

et al. 2021

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Although the sporadic form of Alzheimer’s disease (AD) is the prevalent form, the cellular events underlying the disease pathogenesis have not been fully characterized. Accumulating evidence points to mitochondrial dysfunction as one of the events responsible for AD progression. We investigated mitochondrial function in fibroblasts collected from patients diagnosed with the sporadic form of AD (sAD), placing a particular focus on mitochondrial turnover. We measured mitochondrial biogenesis and autophagic clearance, and evaluated the presence of bioenergetic stress in sAD cells. The mitochondrial turnover was clearly lower in the fibroblasts from sAD patients than in the fibroblasts from the control subjects, and the levels of many proteins regulating mitochondrial biogenesis, autophagy and mitophagy were decreased in patient cells. Additionally, the sAD fibroblasts had slightly higher mitochondrial superoxide levels and impaired antioxidant defense. Mitochondrial turnover undergoes feedback regulation through mitochondrial retrograde signaling, which is responsible for the maintenance of optimal mitochondrial functioning, and mitochondria-derived ROS participate as signaling molecules in this process. Our results showed that in sAD patients cells, there is a shift in the balance of mitochondrial function, possibly in response to the presence of cellular stress related to disease development.

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Section: Discussioncontrasting

confidence: 55%

Section: Discussionmentioning

confidence: 69%

Effect of Chronic Stress Present in Fibroblasts Derived from Patients with a Sporadic Form of AD on Mitochondrial Function and Mitochondrial Turnover

et al. 2021

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“…Additionally, others report slower mitochondria dynamics in sporadic AD fibroblasts due to the downregulation of both fission- and fusion-related proteins [ 97 ]. In further support, Drabik and colleagues [ 98 ] found that, in comparison with control patients, fibroblasts from sporadic AD individuals had lower levels of the fusion-regulating proteins and of Drp1, which were accompanied by a lower rate of mitochondrial fusion–fission. These alterations evoked the appearance of a less branched mitochondrial network characterized by less separated mitochondria that presented a smaller size.…”

Section: Mitochondria (Dys)function In Alzheimer’s Disease: a Brief O...mentioning

confidence: 92%

Current Advances in Mitochondrial Targeted Interventions in Alzheimer’s Disease

Sousa,

Moreira,

Cardoso

2023

Biomedicines

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Alzheimer’s disease is the most prevalent neurodegenerative disorder and affects the lives not only of those who are diagnosed but also of their caregivers. Despite the enormous social, economic and political burden, AD remains a disease without an effective treatment and with several failed attempts to modify the disease course. The fact that AD clinical diagnosis is most often performed at a stage at which the underlying pathological events are in an advanced and conceivably irremediable state strongly hampers treatment attempts. This raises the awareness of the need to identify and characterize the early brain changes in AD, in order to identify possible novel therapeutic targets to circumvent AD’s cascade of events. One of the most auspicious targets is mitochondria, powerful organelles found in nearly all cells of the body. A vast body of literature has shown that mitochondria from AD patients and model organisms of the disease differ from their non-AD counterparts. In view of this evidence, preserving and/or restoring mitochondria’s health and function can represent the primary means to achieve advances to tackle AD. In this review, we will briefly assess and summarize the previous and latest evidence of mitochondria dysfunction in AD. A particular focus will be given to the recent updates and advances in the strategy options aimed to target faulty mitochondria in AD.

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“…The quantifications of LC3 and LAMP1 dots size and count and LysoTracker intensity were assessed using Analyze particles function of Fiji software. Mitochondrial network volume was quantified thanks to 3D object counter plugin of Image J and mitochondria branches length and number as well as end-points and junction number were quantified using skeletonize plugin of Image J 25 . The quantification was obtained from at least 25 cells per patient.…”

Section: 5-mitophagy and Autophagy Analysesmentioning

confidence: 99%

Mitochondria alterations in fibroblasts from sporadic Alzheimer’s disease (AD) patients correlate with AD-related clinical hallmarks

Eysert,

Kinoshita,

Lagarde

et al. 2023

Preprint

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INTRODUCTIONMitochondria dysfunctions are key features in Alzheimer’s disease (AD). The occurrence of these disturbances in AD patient’s peripheral cells and their potential correlation with disease progression are under investigated.METHODSWe studied mitochondrial structure, function and mitophagy in fibroblasts including healthy volunteers and AD patients at the prodromal (AD-MCI) or demented (AD-D) stages. We carried out correlation studies with clinical cognitive scores, Aβ plaques burden and the accumulation of peripheral amyloid precursor protein C-terminal fragments (APP-CTFs).RESULTSWe unveiled progressive alteration of mitochondria structure as well as specific mitochondrial dysfunctions signatures in AD-MCI and AD-D fibroblasts and show defective mitophagy and autophagy linked to impaired lysosomal activity in AD-D fibroblasts. We reported on significant correlations of a subset of these dysfunctions with cognitive decline, AD-related clinical hallmarks and peripheral APP-CTFs accumulation.DISCUSSIONThis study emphasizes the potential use of peripheral cells for investigating AD pathophysiology and likely diagnosis.

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Adaptation of mitochondrial network dynamics and velocity of mitochondrial movement to chronic stress present in fibroblasts derived from patients with sporadic form of Alzheimer’s disease

Cited by 6 publications

References 62 publications

Effect of Chronic Stress Present in Fibroblasts Derived from Patients with a Sporadic Form of AD on Mitochondrial Function and Mitochondrial Turnover

Effect of Chronic Stress Present in Fibroblasts Derived from Patients with a Sporadic Form of AD on Mitochondrial Function and Mitochondrial Turnover

Current Advances in Mitochondrial Targeted Interventions in Alzheimer’s Disease

Mitochondria alterations in fibroblasts from sporadic Alzheimer’s disease (AD) patients correlate with AD-related clinical hallmarks

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