Mitochondrial γ‐secretase participates in the metabolism of mitochondria‐associated amyloid precursor protein

Pavlov, Pavel F.; Wiehager, Birgitta; Sakai, Jun; Frykman, Susanne; Behbahani, Homira; Winblad, Bengt; Ankarcrona, Maria

doi:10.1096/fj.10-157230

Cited by 101 publications

(82 citation statements)

References 44 publications

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“…Conversely, it might derive from mitochondria-associated amyloid beta A4 protein (APP), since there is experimental evidence of localised Ab production by a mitochondrial g-secretase complex (Fig. 1A) [34]. Overall, these findings provide compelling evidence that mitochondriaassociated and/or intra-mitochondrial Ab may directly cause neurotoxicity.…”

Section: Mitochondrial Dysfunction: Oxidative Stressmentioning

confidence: 88%

Towards Alzheimer's root cause: ECSIT as an integrating hub between oxidative stress, inflammation and mitochondrial dysfunction

et al. 2012

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Here we postulate that the adapter protein evolutionarily conserved signalling intermediate in Toll pathway (ECSIT) might act as a molecular sensor in the pathogenesis of Alzheimer's disease (AD). Based on the analysis of our AD‐associated protein interaction network, ECSIT emerges as an integrating signalling hub that ascertains cell homeostasis by the specific activation of protective molecular mechanisms in response to signals of amyloid‐beta or oxidative damage. This converges into a complex cascade of patho‐physiological processes. A failure to repair would generate severe mitochondrial damage and ultimately activate pro‐apoptotic mechanisms, promoting synaptic dysfunction and neuronal death. Further support for our hypothesis is provided by increasing evidence of mitochondrial dysfunction in the disease etiology. Our model integrates seemingly controversial hypotheses for familial and sporadic forms of AD and envisions ECSIT as a biomarker to guide future therapies to halt or prevent AD.Editor's suggested further reading in BioEssays Binding of amyloid peptides to domain‐swapped dimers of other amyloid‐forming protein may prevent their neurotoxicity AbstractPlease, also watch the Video Abstract

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Section: Mitochondrial Dysfunction: Oxidative Stressmentioning

confidence: 88%

Towards Alzheimer's root cause: ECSIT as an integrating hub between oxidative stress, inflammation and mitochondrial dysfunction

et al. 2012

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“…3B and Refs. 34,35), it is possible that the TACE-cleaved Notch fragment could travel to mitochondria, wherein ␥-secretase and MIPEP serve roles analogous to those of mitochondrial processing peptidase and MIPEP in transporting the immediate ␥-secretase substrate derived from Notch (N⌬E), and possibly other membrane proteins, for sequential processing and compartmentalization.…”

Section: Discussionmentioning

confidence: 99%

γ-Secretase-regulated Proteolysis of the Notch Receptor by Mitochondrial Intermediate Peptidase

Lee

Srinivasan

Sephton

et al. 2011

Journal of Biological Chemistry

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Notch is a transmembrane receptor that controls a diverse array of cellular processes including cell proliferation, differentiation, survival, and migration. The cellular outcome of Notch signaling is dependent on extracellular and intracellular signals, but the complexities of its regulation are not well understood. Canonical Notch signaling involves ligand association that triggers sequential and regulated proteolysis of Notch at several sites. Ligand-dependent proteolysis at the S2 site removes the bulk of the extracellular domain of Notch. Subsequent ␥-secretase-mediated intramembrane proteolysis of the remaining membrane-tethered Notch fragment at the S3 site produces a nuclear-destined Notch intracellular domain (NICD). Here we show that following ␥-secretase cleavage, Notch is proteolyzed at a novel S5 site. We have identified this S5 site to be eight amino acids downstream of the S3 site. The Notch signaling pathway is evolutionarily conserved and plays a fundamental role in communication between adjacent cells to influence differentiation, proliferation, survival, and migration (1-3). During its maturation and function as a signal transducer, the Notch receptor undergoes proteolysis by three different enzymes. Notch is processed initially by a furin-like convertase in the trans-Golgi at the S1 site to generate an extracellular domain and a membrane-bound domain, which remain associated during their transport to the plasma membrane.Binding of a ligand to the extracellular domain of Notch stimulates proteolysis of Notch at the S2 site by the metalloprotease tumor necrosis factor ␣-converting enzyme (TACE) and produces a transmembrane fragment referred to as Notch extracellular truncation (N⌬E) 3 (4, 5). The membrane-tethered N⌬E is recruited to the ␥-secretase complex for S3 site cleavage to generate the Notch intracellular domain (NICD) (6 -8). The resultant NICD translocates into the nucleus, where it associates with the transcription factor CBF-1 and with coactivators, such as Mastermind, to initiate gene transcription (9 -12). Notch has mostly been characterized by its transcriptional role in the nucleus, but several studies suggest that it may have functional roles in the cytoplasm (13, 14) as well as in the mitochondria (15)(16)(17)(18)(19)(20) where, in the latter, Notch acts as an interpreter of cellular cues. In this study, we provide evidence that following cleavage by ␥-secretase, NICD is further proteolyzed at a novel S5 site. We identify the protease responsible for this cleavage as the mitochondrial intermediate peptidase (MIPEP), which generates ⌬NICD ( 1752 RQHGQ-…). We showed that Notch function can be modulated by MIPEP-mediated cleavage. Our findings raise the possibility that S5 site proteolysis represents a novel regulatory component of Notch signaling. EXPERIMENTAL PROCEDURES Materials-Chemicals used included ␥-secretase inhibitor N-[N-(3,5-Difluorophenylacetyl)-L-alanyl]-S-phenylglycine t-bu-tyl ester (DAPT) (Calbiochem/EMD) and the EDTA-free complete protease inhibitor mixture tabl...

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“…APP can not only alter mitochondrial function by blocking the mitochondrial protein import system, but can also exert its deleterious effects inside the organelle. In cultured SH-SY5Y cells, APP was shown to be a substrate of the mitochondrial γ-secretase, where APP processing would lead to local Aβ production inside mitochondria, thus contributing to the organelle dysfunction (Pavlov et al, 2011). Direct import of Aβ into the inner mitochondrial membrane has also been reported in Aβ-treated rat mitochondria (Hansson Petersen et al, 2008).…”

Section: In Alzheimer´s Diseasementioning

confidence: 99%

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

Morán

Moreno-Lastres

Marín-Buera

et al. 2012

Free Radical Biology and Medicine

140

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For decades mitochondria have been considered static round shaped organelles in charge of energy production. On the contrary, they are highly dynamic cellular components that undergo continuous cycles of fusion and fission influenced, for instance, by oxidative stress, cellular energy requirements, or the cell cycle state. New important functions beyond energy production have been attributed to mitochondria, such as the regulation of cell survival due to their role in the modulation of apoptosis, autophagy and aging. Primary mitochondrial diseases due to mutations in genes involved in these new mitochondrial functions, and the implication of mitochondrial dysfunction in multifactorial human pathologies like cancer, Alzheimer's and Parkinson's diseases, or diabetes has been demonstrated. Therefore, mitochondria are set at a central point of the equilibrium between health and disease, and a better understanding of mitochondrial functions will open new fields to explore the role of these mitochondrial pathways in human pathologies. The present review will dissect the relationships between the activity and assembly defects of the mitochondrial respiratory chain, oxidative damage, and alterations in mitochondrial dynamics, with special focus at their implications in neurodegeneration.

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Mitochondrial γ‐secretase participates in the metabolism of mitochondria‐associated amyloid precursor protein

Cited by 101 publications

References 44 publications

Towards Alzheimer's root cause: ECSIT as an integrating hub between oxidative stress, inflammation and mitochondrial dysfunction

Towards Alzheimer's root cause: ECSIT as an integrating hub between oxidative stress, inflammation and mitochondrial dysfunction

γ-Secretase-regulated Proteolysis of the Notch Receptor by Mitochondrial Intermediate Peptidase

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

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