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Amyloid-Beta interaction with mitochondria.

Pagani L, Eckert A - Int J Alzheimers Dis (2011)

Bottom Line: In this paper, we will outline current knowledge of the intracellular localization of both Aβ and AβPP addressing the question of how Aβ can access mitochondria.In particular, we focus on Aβ interaction with different mitochondrial targets including the outer mitochondrial membrane, intermembrane space, inner mitochondrial membrane, and the matrix.Thus, this paper establishes a modified model of the Alzheimer cascade mitochondrial hypothesis.

View Article: PubMed Central - PubMed

Affiliation: Neurobiology Laboratory for Brain Aging and Mental Health, Psychiatric University Clinics, University of Basel, Wilhelm Klein-Straße 27, 4012 Basel, Switzerland.

ABSTRACT
Mitochondrial dysfunction is a hallmark of amyloid-beta(Aβ)-induced neuronal toxicity in Alzheimer's disease (AD). The recent emphasis on the intracellular biology of Aβ and its precursor protein (AβPP) has led researchers to consider the possibility that mitochondria-associated and/or intramitochondrial Aβ may directly cause neurotoxicity. In this paper, we will outline current knowledge of the intracellular localization of both Aβ and AβPP addressing the question of how Aβ can access mitochondria. Moreover, we summarize evidence from AD postmortem brain as well as cellular and animal AD models showing that Aβ triggers mitochondrial dysfunction through a number of pathways such as impairment of oxidative phosphorylation, elevation of reactive oxygen species (ROS) production, alteration of mitochondrial dynamics, and interaction with mitochondrial proteins. In particular, we focus on Aβ interaction with different mitochondrial targets including the outer mitochondrial membrane, intermembrane space, inner mitochondrial membrane, and the matrix. Thus, this paper establishes a modified model of the Alzheimer cascade mitochondrial hypothesis.

No MeSH data available.


Related in: MedlinePlus

Mitochondrial targets of Aβ. Aβ associated with mitochondria may be deposited at several locations. Although not present exclusively on the outer mitochondrial membrane, Aβ that might be present at that site might influence the interaction of multiple cytosolic proteins (including those of the bcl2 family) with mitochondria, as well as affect the receptor binding of cargo targeted for import into the organelle via the TOM import machinery impeding mitochondrial entry to neosynthesised nuclear-encoded proteins such as subunits of the electron transport chain (ETC) complex IV (CIV). In the intramembrane space, Aβ might affect the functions of both the inner and outer mitochondrial membrane by multiple mechanisms including modulating their permeability. In the mitochondrial matrix, Aβ might interact with important components of metabolic or antioxidant mechanisms. The interaction of Aβ with the inner mitochondrial membrane would bring it into contact with respiratory chain complexes with the potential for myriad effects on cellular metabolism. Thus, Aβ affects the activity of several enzymes, such as pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (α-KGDH), decreasing NADH reduction, and the ETC enzyme CIV, reducing the amount of hydrogen that is translocated from the matrix to the intermembrane space, thus impairing the mitochondrial membrane potential (MMP). The dysfunction of the ETC leads to a decreased CV activity and so to a lower ATP synthesis, in addition to increasing reactive oxygen species (ROS) production. ROS negatively influences presequence P (PreP) activity, blocking Aβ degradation, exacerbating mitochondrial Aβ presence. Moreover, ROS induce peroxidation of several mitochondrial macromolecules, such as mitochondrial DNA (mtDNA) and mitochondrial lipids, additionally impairing mitochondrial function. Aβ binds NAD+ pocket in ABAD, blocking its activity and inducing further ROS production. Aβ also influences mitochondrial dynamic, by improving Fis1 presence and activity, thus increasing mitochondrial fragmentation (fission protein: Fis1; fusion proteins: Mfn1/2 and OPA1). Furthermore, Aβ binding to cyclophilin D (CypD) enhances the protein translocation to the inner membrane, favouring the opening of the mitochondrial permeability transition pore, formed by ANT and VDAC. Calcium storage in mitochondria is impaired, altering neuronal function; calcium is exported to the cytosol, as well as other apoptotic factors (ProAp) such as cytochrome c, apoptosis-inducing factor, Smac/DIABLO, endonuclease G, and procaspases, activating cellular apoptosis. IMM: inner mitochondrial membrane, IMS: intermembrane space, OMM: outer mitochondrial membrane.
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Related In: Results  -  Collection


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fig2: Mitochondrial targets of Aβ. Aβ associated with mitochondria may be deposited at several locations. Although not present exclusively on the outer mitochondrial membrane, Aβ that might be present at that site might influence the interaction of multiple cytosolic proteins (including those of the bcl2 family) with mitochondria, as well as affect the receptor binding of cargo targeted for import into the organelle via the TOM import machinery impeding mitochondrial entry to neosynthesised nuclear-encoded proteins such as subunits of the electron transport chain (ETC) complex IV (CIV). In the intramembrane space, Aβ might affect the functions of both the inner and outer mitochondrial membrane by multiple mechanisms including modulating their permeability. In the mitochondrial matrix, Aβ might interact with important components of metabolic or antioxidant mechanisms. The interaction of Aβ with the inner mitochondrial membrane would bring it into contact with respiratory chain complexes with the potential for myriad effects on cellular metabolism. Thus, Aβ affects the activity of several enzymes, such as pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (α-KGDH), decreasing NADH reduction, and the ETC enzyme CIV, reducing the amount of hydrogen that is translocated from the matrix to the intermembrane space, thus impairing the mitochondrial membrane potential (MMP). The dysfunction of the ETC leads to a decreased CV activity and so to a lower ATP synthesis, in addition to increasing reactive oxygen species (ROS) production. ROS negatively influences presequence P (PreP) activity, blocking Aβ degradation, exacerbating mitochondrial Aβ presence. Moreover, ROS induce peroxidation of several mitochondrial macromolecules, such as mitochondrial DNA (mtDNA) and mitochondrial lipids, additionally impairing mitochondrial function. Aβ binds NAD+ pocket in ABAD, blocking its activity and inducing further ROS production. Aβ also influences mitochondrial dynamic, by improving Fis1 presence and activity, thus increasing mitochondrial fragmentation (fission protein: Fis1; fusion proteins: Mfn1/2 and OPA1). Furthermore, Aβ binding to cyclophilin D (CypD) enhances the protein translocation to the inner membrane, favouring the opening of the mitochondrial permeability transition pore, formed by ANT and VDAC. Calcium storage in mitochondria is impaired, altering neuronal function; calcium is exported to the cytosol, as well as other apoptotic factors (ProAp) such as cytochrome c, apoptosis-inducing factor, Smac/DIABLO, endonuclease G, and procaspases, activating cellular apoptosis. IMM: inner mitochondrial membrane, IMS: intermembrane space, OMM: outer mitochondrial membrane.

Mentions: Mitochondria are composed of a double lipid membrane which structures four compartments, distinct by composition and function. The porous outer membrane (OMM) encompasses the whole organelle. It contains many proteins like import complexes and voltage-dependent anion channels (VDAC) responsible for the free passage of low molecular weight substances (up to 5000 Da) between the cytoplasm and the intermembrane space (IMS) (Figures 1 and 2) which represents a reservoir of protons establishing a proton electrochemical gradient across IMM that is needed for the production of ATP via ATPase (complex V). IMS contains proapoptotic proteins like cytochrome c, Smac/Diablo, EndoG, and Htra2/Omi. In contrast to the permeable OMM, the inner mitochondrial membrane (IMM), rich in cardiolipin, provides a highly efficient barrier to the flow of small molecules and ions, including protons. This membrane is invaginated into numerous cristae increasing cell surface area. It houses the respiratory enzymes of the electron transport chain (ETC), the cofactor coenzyme Q, and many mitochondrial carriers. In the matrix, different metabolic pathways take place including the tricarboxylic (TCA or Krebs) cycle (Figure 2).


Amyloid-Beta interaction with mitochondria.

Pagani L, Eckert A - Int J Alzheimers Dis (2011)

Mitochondrial targets of Aβ. Aβ associated with mitochondria may be deposited at several locations. Although not present exclusively on the outer mitochondrial membrane, Aβ that might be present at that site might influence the interaction of multiple cytosolic proteins (including those of the bcl2 family) with mitochondria, as well as affect the receptor binding of cargo targeted for import into the organelle via the TOM import machinery impeding mitochondrial entry to neosynthesised nuclear-encoded proteins such as subunits of the electron transport chain (ETC) complex IV (CIV). In the intramembrane space, Aβ might affect the functions of both the inner and outer mitochondrial membrane by multiple mechanisms including modulating their permeability. In the mitochondrial matrix, Aβ might interact with important components of metabolic or antioxidant mechanisms. The interaction of Aβ with the inner mitochondrial membrane would bring it into contact with respiratory chain complexes with the potential for myriad effects on cellular metabolism. Thus, Aβ affects the activity of several enzymes, such as pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (α-KGDH), decreasing NADH reduction, and the ETC enzyme CIV, reducing the amount of hydrogen that is translocated from the matrix to the intermembrane space, thus impairing the mitochondrial membrane potential (MMP). The dysfunction of the ETC leads to a decreased CV activity and so to a lower ATP synthesis, in addition to increasing reactive oxygen species (ROS) production. ROS negatively influences presequence P (PreP) activity, blocking Aβ degradation, exacerbating mitochondrial Aβ presence. Moreover, ROS induce peroxidation of several mitochondrial macromolecules, such as mitochondrial DNA (mtDNA) and mitochondrial lipids, additionally impairing mitochondrial function. Aβ binds NAD+ pocket in ABAD, blocking its activity and inducing further ROS production. Aβ also influences mitochondrial dynamic, by improving Fis1 presence and activity, thus increasing mitochondrial fragmentation (fission protein: Fis1; fusion proteins: Mfn1/2 and OPA1). Furthermore, Aβ binding to cyclophilin D (CypD) enhances the protein translocation to the inner membrane, favouring the opening of the mitochondrial permeability transition pore, formed by ANT and VDAC. Calcium storage in mitochondria is impaired, altering neuronal function; calcium is exported to the cytosol, as well as other apoptotic factors (ProAp) such as cytochrome c, apoptosis-inducing factor, Smac/DIABLO, endonuclease G, and procaspases, activating cellular apoptosis. IMM: inner mitochondrial membrane, IMS: intermembrane space, OMM: outer mitochondrial membrane.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig2: Mitochondrial targets of Aβ. Aβ associated with mitochondria may be deposited at several locations. Although not present exclusively on the outer mitochondrial membrane, Aβ that might be present at that site might influence the interaction of multiple cytosolic proteins (including those of the bcl2 family) with mitochondria, as well as affect the receptor binding of cargo targeted for import into the organelle via the TOM import machinery impeding mitochondrial entry to neosynthesised nuclear-encoded proteins such as subunits of the electron transport chain (ETC) complex IV (CIV). In the intramembrane space, Aβ might affect the functions of both the inner and outer mitochondrial membrane by multiple mechanisms including modulating their permeability. In the mitochondrial matrix, Aβ might interact with important components of metabolic or antioxidant mechanisms. The interaction of Aβ with the inner mitochondrial membrane would bring it into contact with respiratory chain complexes with the potential for myriad effects on cellular metabolism. Thus, Aβ affects the activity of several enzymes, such as pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (α-KGDH), decreasing NADH reduction, and the ETC enzyme CIV, reducing the amount of hydrogen that is translocated from the matrix to the intermembrane space, thus impairing the mitochondrial membrane potential (MMP). The dysfunction of the ETC leads to a decreased CV activity and so to a lower ATP synthesis, in addition to increasing reactive oxygen species (ROS) production. ROS negatively influences presequence P (PreP) activity, blocking Aβ degradation, exacerbating mitochondrial Aβ presence. Moreover, ROS induce peroxidation of several mitochondrial macromolecules, such as mitochondrial DNA (mtDNA) and mitochondrial lipids, additionally impairing mitochondrial function. Aβ binds NAD+ pocket in ABAD, blocking its activity and inducing further ROS production. Aβ also influences mitochondrial dynamic, by improving Fis1 presence and activity, thus increasing mitochondrial fragmentation (fission protein: Fis1; fusion proteins: Mfn1/2 and OPA1). Furthermore, Aβ binding to cyclophilin D (CypD) enhances the protein translocation to the inner membrane, favouring the opening of the mitochondrial permeability transition pore, formed by ANT and VDAC. Calcium storage in mitochondria is impaired, altering neuronal function; calcium is exported to the cytosol, as well as other apoptotic factors (ProAp) such as cytochrome c, apoptosis-inducing factor, Smac/DIABLO, endonuclease G, and procaspases, activating cellular apoptosis. IMM: inner mitochondrial membrane, IMS: intermembrane space, OMM: outer mitochondrial membrane.
Mentions: Mitochondria are composed of a double lipid membrane which structures four compartments, distinct by composition and function. The porous outer membrane (OMM) encompasses the whole organelle. It contains many proteins like import complexes and voltage-dependent anion channels (VDAC) responsible for the free passage of low molecular weight substances (up to 5000 Da) between the cytoplasm and the intermembrane space (IMS) (Figures 1 and 2) which represents a reservoir of protons establishing a proton electrochemical gradient across IMM that is needed for the production of ATP via ATPase (complex V). IMS contains proapoptotic proteins like cytochrome c, Smac/Diablo, EndoG, and Htra2/Omi. In contrast to the permeable OMM, the inner mitochondrial membrane (IMM), rich in cardiolipin, provides a highly efficient barrier to the flow of small molecules and ions, including protons. This membrane is invaginated into numerous cristae increasing cell surface area. It houses the respiratory enzymes of the electron transport chain (ETC), the cofactor coenzyme Q, and many mitochondrial carriers. In the matrix, different metabolic pathways take place including the tricarboxylic (TCA or Krebs) cycle (Figure 2).

Bottom Line: In this paper, we will outline current knowledge of the intracellular localization of both Aβ and AβPP addressing the question of how Aβ can access mitochondria.In particular, we focus on Aβ interaction with different mitochondrial targets including the outer mitochondrial membrane, intermembrane space, inner mitochondrial membrane, and the matrix.Thus, this paper establishes a modified model of the Alzheimer cascade mitochondrial hypothesis.

View Article: PubMed Central - PubMed

Affiliation: Neurobiology Laboratory for Brain Aging and Mental Health, Psychiatric University Clinics, University of Basel, Wilhelm Klein-Straße 27, 4012 Basel, Switzerland.

ABSTRACT
Mitochondrial dysfunction is a hallmark of amyloid-beta(Aβ)-induced neuronal toxicity in Alzheimer's disease (AD). The recent emphasis on the intracellular biology of Aβ and its precursor protein (AβPP) has led researchers to consider the possibility that mitochondria-associated and/or intramitochondrial Aβ may directly cause neurotoxicity. In this paper, we will outline current knowledge of the intracellular localization of both Aβ and AβPP addressing the question of how Aβ can access mitochondria. Moreover, we summarize evidence from AD postmortem brain as well as cellular and animal AD models showing that Aβ triggers mitochondrial dysfunction through a number of pathways such as impairment of oxidative phosphorylation, elevation of reactive oxygen species (ROS) production, alteration of mitochondrial dynamics, and interaction with mitochondrial proteins. In particular, we focus on Aβ interaction with different mitochondrial targets including the outer mitochondrial membrane, intermembrane space, inner mitochondrial membrane, and the matrix. Thus, this paper establishes a modified model of the Alzheimer cascade mitochondrial hypothesis.

No MeSH data available.


Related in: MedlinePlus