Mitochondrial respiratory chain Complexes I and IV are impaired by β-amyloid via direct interaction and through Complex I-dependent ROS production, respectively

Bobba, Antonella; Amadoro, Giuseppina; Valenti, Daniela; Corsetti, Veronica; Lassandro, Rocco; Atlante, Anna

doi:10.1016/j.mito.2013.03.008

Cited by 125 publications

(101 citation statements)

References 79 publications

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“…fragmentation and reduced O 2 consumption) in peripheral cells [92] and mice [93]. Either Aβ or ceramide independently provoke respiratory chain malfunction in vitro [30,94]. It has been suggested that ceramide alone induces mitochondrial dysfunction through mitochondrial depolarization and mitochondrial outer membrane permeabilization, contributing to the initiation of mitochondria-dependent apoptosis [95].…”

Section: Discussionmentioning

confidence: 99%

“…Complex IV (Cytochrome C oxidase, COX) is particularly affected in AD brain [26,27], AD cybrids [28] and treated cells [22,29]. There is also work citing Complex I or III are additionally targeted [16,30]. We found that intracellular Aβ disrupts the insulin signaling cascade [31], cellular Ca2+ homeostasis [32], and mitochondrial oxidative phosphorylation [33], but until now have not investigated some of their relationships.…”

Section: Introductionmentioning

confidence: 89%

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Synergistic effects of β-amyloid and ceramide-induced insulin resistance on mitochondrial metabolism in neuronal cells

Kwon

Gamache

Lee

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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A large body of evidence support major roles of mitochondrial dysfunction and insulin action in the Alzheimer's disease (AD) brain. However, interaction between cellular expression of β-amyloid (Aβ) and insulin resistance on mitochondrial metabolism has not been explored in neuronal cells. We investigated the additive and synergistic effects of intracellular Aβ42 and ceramide-induced insulin resistance on mitochondrial metabolism in SH-SY5Y and Neuro-2a cells. In our model, mitochondria take-up Aβ42 expressed through viral-mediated transfection and exposure of the same cells to ceramide produces resistance to insulin signaling. Ceramide alone increased phosphorylated MAP kinases while decreasing phospho-Akt (Ser473). The combination of Aβ42 and ceramide synergistically decreased phospho-Thr308 on Akt. Aβ42 and ceramide synergistically also decreased mitochondrial complex III activity and ATP generation whereas Aβ alone was largely responsible for complex IV inhibition and increases in mitochondrial reactive oxygen species production (ROS). Proteomic analysis showed that a number of mitochondrial respiratory chain and tricarboxylic acid cycle enzymes were additively or synergistically decreased by ceramide in combination with Aβ42 expression. Mitochondrial fusion and fission proteins were notably dysregulated by Aβ42 (Mfn1) or Aβ42 plus ceramide (OPA1, Drp1). Antioxidant vitamins blocked the Aβ42 alone-induced ROS production, but did not reverse Aβ42-induced ATP reduction or complex IV inhibition. Aβ expression combined with ceramide exposure had additive effects to decrease cell viability. Taken together, our data demonstrate that Aβ42 expression and ceramide-induced insulin resistance synergistically interact to exacerbate mitochondrial damage and that therapeutic efforts to reduce insulin resistance could lessen failures of energy production and mitochondrial dynamics.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 89%

Synergistic effects of β-amyloid and ceramide-induced insulin resistance on mitochondrial metabolism in neuronal cells

Kwon

Gamache

Lee

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…The direct interaction between Aβ and Complex I was described in two independent studies and the C-terminal sequence of the ND3 subunit was identified as the binding site for Aβ1-42 [65,67]. Aβ was shown to inhibit Complex I activity and to increase Complex I-dependent production of ROS, which in turn lead to mitochondrial dysfunction.…”

Section: Complex Imentioning

confidence: 98%

“…The reduced equivalents of NADH and FADH 2 derived from the oxidation of carbohydrates and fatty acids flow from Complex I through Complex IV via a series of oxidation-reduction events. The energy, released during the process, charges the inner mitochondrial membrane and drives ATPase (Complex V) to synthesize ATP from ADP and inorganic phosphate [65].…”

Section: Electron Transport Chain (Etc)mentioning

confidence: 99%

“…Aβ was shown to inhibit Complex I activity and to increase Complex I-dependent production of ROS, which in turn lead to mitochondrial dysfunction. However, even when a mitochondrial defect can be attributed to Complex I, it is hard to determine whether the effects observed arise from a loss of Complex I activity, an increase in its ROS production, or both [65].…”

Section: Complex Imentioning

confidence: 99%

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A Direct Interaction Between Mitochondrial Proteins and Amyloid-β Peptide and its Significance for the Progression and Treatment of Alzheimer’s Disease

Benek¹,

Aitken²,

Hroch³

et al. 2015

CMC

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Abstract:The amyloid-β peptide (Aβ) has been associated with Alzheimer's disease (AD) for decades. The original amyloid cascade hypothesis declared that the insoluble extracellular plaques were responsible for Aβ toxicity. Later, this hypothesis has been updated and soluble intracellular Aβ forms and their effects within the cell have come into focus. Mitochondrial dysfunction plays an important role in the pathophysiology of AD. Aβ was detected inside mitochondria and several mitochondrial proteins were found to interact directly with Aβ. Such interactions can affect a protein's function and cause damage to the mitochondria and finally to the whole cell. This review summarizes the current knowledge of mitochondrial proteins directly interacting with Aβ and discusses their significance for the development of therapeutics in the treatment of AD.

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The Effect of Reactive Oxygen Species on Respiratory Complex I Activity in Liposomes

Eisermann,

Liang,

Wright

et al. 2024

Chemistry A European J

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Respiratory complex I (R‐CI) is an essential enzyme in the mitochondrial electron transport chain but also a major source of reactive oxygen species (ROS), which are implicated in neurodegenerative diseases and ageing. While the mechanism of ROS production by R‐CI is well‐established, the feedback of ROS on R‐CI activity is poorly understood. Here, we perform EPR spectroscopy on R‐CI incorporated in artificial membrane vesicles to reveal that ROS (particularly hydroxyl radicals) reduce R‐CI activity by making the membrane more polar and by increasing its hydrogen bonding capability. Moreover, the mechanism that we have uncovered reveals that the feedback of ROS on R‐CI activity via the membrane is transient and not permanent; lipid peroxidation is negligible for the levels of ROS generated under these conditions. Our successful use of modular proteoliposome systems in conjunction with EPR spectroscopy and other biophysical techniques is a powerful approach for investigating ROS effects on other membrane proteins.

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Mitochondrial respiratory chain Complexes I and IV are impaired by β-amyloid via direct interaction and through Complex I-dependent ROS production, respectively

Cited by 125 publications

References 79 publications

Synergistic effects of β-amyloid and ceramide-induced insulin resistance on mitochondrial metabolism in neuronal cells

Synergistic effects of β-amyloid and ceramide-induced insulin resistance on mitochondrial metabolism in neuronal cells

A Direct Interaction Between Mitochondrial Proteins and Amyloid-β Peptide and its Significance for the Progression and Treatment of Alzheimer’s Disease

The Effect of Reactive Oxygen Species on Respiratory Complex I Activity in Liposomes

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Mitochondrial respiratory chain Complexes I and IV are impaired by β-amyloid via direct interaction and through Complex I-dependent ROS production, respectively

Cited by 125 publications

References 79 publications

Synergistic effects of β-amyloid and ceramide-induced insulin resistance on mitochondrial metabolism in neuronal cells

Synergistic effects of β-amyloid and ceramide-induced insulin resistance on mitochondrial metabolism in neuronal cells

A Direct Interaction Between Mitochondrial Proteins and Amyloid-&#946; Peptide and its Significance for the Progression and Treatment of Alzheimer&#8217;s Disease

The Effect of Reactive Oxygen Species on Respiratory Complex I Activity in Liposomes

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A Direct Interaction Between Mitochondrial Proteins and Amyloid-β Peptide and its Significance for the Progression and Treatment of Alzheimer’s Disease