Mechanisms of mitochondrial dysfunction and energy deficiency in Alzheimer’s disease
Abstract
Several studies have demonstrated aberrations in the Electron Transport Complexes (ETC) and Krebs (TCA) cycle in Alzheimer's disease (AD) brain. Optimal activity of these key metabolic pathways depends on several redox active centers and metabolites including heme, coenzyme Q, iron-sulfur, vitamins, minerals, and micronutrients. Disturbed heme metabolism leads to increased aberrations in the ETC (loss of complex IV), dimerization of APP, free radical production, markers of oxidative damage, and ultimately cell death all of which represent key cytopathologies in AD. The mechanism of mitochondrial dysfunction in AD is controversial. The observations that Abeta is found both in the cells and in the mitochondria and that Abeta binds with heme may provide clues to this mechanism. Mitochondrial Abeta may interfere with key metabolites or metabolic pathways in a manner that overwhelms the mitochondrial mechanisms of repair. Identifying the molecular mechanism for how Abeta interferes with mitochondria and that explains the established key cytopathologies in AD may also suggest molecular targets for therapeutic interventions. Below we review recent studies describing the possible role of Abeta in altered energy production through heme metabolism. We further discuss how protecting mitochondria could confer resistance to oxidative and environmental insults. Therapies targeted at protecting mitochondria may improve the clinical outcome of AD patients.
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APP is directly involved in the inhibition of mitophagy.
“It is directly involved in the inhibition of mitophagy (27,39), which was seen in the tumor-infiltrating lymphocytes in both in vivo tumor models (Figure 1).”
From Alzheimer's Disease–Associated Amyloid-β Precursor Protein Prevents Aging Stress–Induced Mitophagy and Fumarate Depletion to Improve Antitumor Immunity (2025) · cites this paper as [39]
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- Authors
- Atamna, H., & Frey, W. H.
- Affiliations
- Regions Hospital (US)
- Corresponding author
- Atamna, Hani
- Frey, William H.
- ORCID
- Frey, William H.
- Venue
- Mitochondrion
- Publisher
- Elsevier BV
- Published
- 2007-09
- Volume
- 7
- Issue
- 5
- Pages
- 297-310
- ISSN
- 1567-7249 (ISSN-L)
- OpenAlex
- W2073268517
- Cited by
- 278
- References
- 17
- Citations by year
- 2026: 3 · 2025: 15 · 2024: 12 · 2023: 10 · 2022: 13 · 2021: 17 · 2020: 20 · 2019: 12 · 2018: 11 · 2017: 9 · 2016: 14 · 2015: 14 · 2014: 15 · 2013: 14 · 2012: 25
- FWCI
- 1.87
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Mitochondrion (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, mitochondrial dysfunction, energy deficiency, amyloid-beta, heme metabolism, electron transport chain, TCA cycle, oxidative stress, iron-sulfur clusters, coenzyme Q10, mitochondrial protection, therapeutic target
- MeSH terms
- Alzheimer Disease, Apolipoproteins E, Brain, Cells, Cultured, Citric Acid Cycle, Energy Metabolism, Free Radicals, Heme, Humans, Mitochondria, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Electron Transport Chain Complex Proteins
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