Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

Marta Pera, Delfina Larrea, Cristina Guardia-Laguarta, Jorge Montesinos, Kevin R. Velasco, Rishi R. Agrawal, Yimeng Xu, Robin B. Chan, Gilbert Di Paolo, Mark F. Mehler, Geoffrey S. Perumal, Frank P. Macaluso, Zachary Z. Freyberg, Rebeca Acin-Perez, Jose Antonio Enriquez, Eric A. Schon, Estela Area-Gomez

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

In the amyloidogenic pathway associated with Alzheimer disease (AD), the amyloid precursor protein (APP) is cleaved by β-secretase to generate a 99-aa C-terminal fragment (C99) that is then cleaved by γ-secretase to generate the β-amyloid (Aβ) found in senile plaques. In previous reports, we and others have shown that γ-secretase activity is enriched in mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) and that ER-mitochondrial connectivity and MAM function are upregulated in AD. We now show that C99, in addition to its localization in endosomes, can also be found in MAM, where it is normally processed rapidly by γ-secretase. In cell models of AD, however, the concentration of unprocessed C99 increases in MAM regions, resulting in elevated sphingolipid turnover and an altered lipid composition of both MAM and mitochondrial membranes. In turn, this change in mitochondrial membrane composition interferes with the proper assembly and activity of mitochondrial respiratory supercomplexes, thereby likely contributing to the bioenergetic defects characteristic of AD.

Original languageEnglish (US)
JournalEMBO Journal
DOIs
StateAccepted/In press - 2017

Fingerprint

Amyloid Precursor Protein Secretases
Mitochondria
Amyloid beta-Protein Precursor
Mitochondrial Membranes
Endoplasmic Reticulum
Alzheimer Disease
Membranes
Sphingolipids
Endosomes
Amyloid Plaques
Chemical analysis
Amyloid
Energy Metabolism
Lipids
Defects

Keywords

  • MAM
  • Alzheimer's disease
  • C99
  • Mitochondria and sphingolipids

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Pera, M., Larrea, D., Guardia-Laguarta, C., Montesinos, J., Velasco, K. R., Agrawal, R. R., ... Area-Gomez, E. (Accepted/In press). Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease. EMBO Journal. https://doi.org/10.15252/embj.201796797

Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease. / Pera, Marta; Larrea, Delfina; Guardia-Laguarta, Cristina; Montesinos, Jorge; Velasco, Kevin R.; Agrawal, Rishi R.; Xu, Yimeng; Chan, Robin B.; Di Paolo, Gilbert; Mehler, Mark F.; Perumal, Geoffrey S.; Macaluso, Frank P.; Freyberg, Zachary Z.; Acin-Perez, Rebeca; Enriquez, Jose Antonio; Schon, Eric A.; Area-Gomez, Estela.

In: EMBO Journal, 2017.

Research output: Contribution to journalArticle

Pera, M, Larrea, D, Guardia-Laguarta, C, Montesinos, J, Velasco, KR, Agrawal, RR, Xu, Y, Chan, RB, Di Paolo, G, Mehler, MF, Perumal, GS, Macaluso, FP, Freyberg, ZZ, Acin-Perez, R, Enriquez, JA, Schon, EA & Area-Gomez, E 2017, 'Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease', EMBO Journal. https://doi.org/10.15252/embj.201796797
Pera, Marta ; Larrea, Delfina ; Guardia-Laguarta, Cristina ; Montesinos, Jorge ; Velasco, Kevin R. ; Agrawal, Rishi R. ; Xu, Yimeng ; Chan, Robin B. ; Di Paolo, Gilbert ; Mehler, Mark F. ; Perumal, Geoffrey S. ; Macaluso, Frank P. ; Freyberg, Zachary Z. ; Acin-Perez, Rebeca ; Enriquez, Jose Antonio ; Schon, Eric A. ; Area-Gomez, Estela. / Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease. In: EMBO Journal. 2017.
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abstract = "In the amyloidogenic pathway associated with Alzheimer disease (AD), the amyloid precursor protein (APP) is cleaved by β-secretase to generate a 99-aa C-terminal fragment (C99) that is then cleaved by γ-secretase to generate the β-amyloid (Aβ) found in senile plaques. In previous reports, we and others have shown that γ-secretase activity is enriched in mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) and that ER-mitochondrial connectivity and MAM function are upregulated in AD. We now show that C99, in addition to its localization in endosomes, can also be found in MAM, where it is normally processed rapidly by γ-secretase. In cell models of AD, however, the concentration of unprocessed C99 increases in MAM regions, resulting in elevated sphingolipid turnover and an altered lipid composition of both MAM and mitochondrial membranes. In turn, this change in mitochondrial membrane composition interferes with the proper assembly and activity of mitochondrial respiratory supercomplexes, thereby likely contributing to the bioenergetic defects characteristic of AD.",
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AU - Larrea, Delfina

AU - Guardia-Laguarta, Cristina

AU - Montesinos, Jorge

AU - Velasco, Kevin R.

AU - Agrawal, Rishi R.

AU - Xu, Yimeng

AU - Chan, Robin B.

AU - Di Paolo, Gilbert

AU - Mehler, Mark F.

AU - Perumal, Geoffrey S.

AU - Macaluso, Frank P.

AU - Freyberg, Zachary Z.

AU - Acin-Perez, Rebeca

AU - Enriquez, Jose Antonio

AU - Schon, Eric A.

AU - Area-Gomez, Estela

PY - 2017

Y1 - 2017

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