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Cited by 235Mitochondrial Function and PathologyAlzheimer's disease research and treatmentsAutophagy in Disease and Therapy

A key role for MAM in mediating mitochondrial dysfunction in Alzheimer disease

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Area-Gomez, Estela, de Groof, Ad, Bonilla, Eduardo, Montesinos, Jorge, Tanji, Kurenai, Boldogh, Istvan, Pon, Liza, Schon, Eric A.·2018·Cell Death & Disease
DOI 10.1038/s41419-017-0215-0PMC PMC5832428
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Abstract

In the last few years, increased emphasis has been devoted to understanding the contribution of mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) to human pathology in general, and neurodegenerative diseases in particular. A major reason for this is the central role that this subdomain of the ER plays in metabolic regulation and in mitochondrial biology. As such, aberrant MAM function may help explain the seemingly unrelated metabolic abnormalities often seen in neurodegeneration. In the specific case of Alzheimer disease (AD), besides perturbations in calcium and lipid homeostasis, there are numerous documented alterations in mitochondrial behavior and function, including reduced respiratory chain activity and oxidative phosphorylation, increased free radical production, and altered organellar morphology, dynamics, and positioning (especially perinuclear mitochondria). However, whether these alterations are primary events causative of the disease, or are secondary downstream events that are the result of some other, more fundamental problem, is still unclear. In support of the former possibility, we recently reported that C99, the C-terminal processing product of the amyloid precursor protein (APP) derived from its cleavage by β-secretase, is present in MAM, that its level is increased in AD, and that this increase reduces mitochondrial respiration, likely via a C99-induced alteration in cellular sphingolipid homeostasis. Thus, the metabolic disturbances seen in AD likely arise from increased ER-mitochondrial communication that is driven by an increase in the levels of C99 at the MAM.

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Cited by

Sorted by citations

Authors
Area-Gomez, E., de Groof, A., Bonilla, E., Montesinos, J., Tanji, K., Boldogh, I., Pon, L., & Schon, E. A.
Affiliations
  • Columbia University (US)
  • Columbia University Irving Medical Center (US)
Corresponding author
Schon, Eric A.
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2018-02-28
Volume
9
Issue
3
Pages
335-335
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/s41419-017-0215-0
PMC
PMC5832428
OpenAlex
W2789816844
Cited by
235
References
16
Citations by year
2026: 20 · 2025: 29 · 2024: 25 · 2023: 26 · 2022: 23 · 2021: 33 · 2020: 33 · 2019: 31 · 2018: 15
FWCI
2.80
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Disease (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • U.S. Department of Defense (W911F-15-1-0169)
  • J. Willard and Alice S. Marriott Foundation
  • National Institutes of Health (5r01ag056387-02)
  • National Institute on Aging (K01AG045335, R01-AG056387)
  • National Institute of General Medical Sciences (R01GM045735, R35GM122589)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
mitochondria-associated endoplasmic reticulum membranes, Alzheimer's disease, mitochondrial dysfunction, C99, amyloid precursor protein, beta-secretase, sphingolipid homeostasis, mitochondrial respiration, oxidative phosphorylation, ER-mitochondria communication, neurodegeneration, calcium homeostasis, lipid homeostasis
MeSH terms
Alzheimer Disease, Animals, Endoplasmic Reticulum, Humans, Mitochondria, Amyloid beta-Protein Precursor, Mitochondrial Membranes, Amyloid Precursor Protein Secretases

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