The Causal Role of Lipoxidative Damage in Mitochondrial Bioenergetic Dysfunction Linked to Alzheimer’s Disease Pathology
Abstract
:1. Introduction
2. The Alzheimer’s Disease Pathology
3. The Entorhinal Cortex as Starting Point
3.1. Selective Neuronal Vulnerability of the Human Entorhinal Cortex
3.2. The Entorhinal Cortex during Physiological Aging
4. The Entorhinal Cortex in AD
4.1. Early Bioenergetic Defects
4.2. ATP Synthase as the Key Target of AD
4.3. Advanced Effects in the Early Stage Resulting from Mitochondrial Dysfunction and Oxidative-Derived Damage
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
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ID (Entry Human) | Protein | Gene | Biological Process | Reference |
---|---|---|---|---|
Q99798 | Aconitate hydratase | ACO2 | Energy metabolism (TCA cycle) | [151,155,156,157,158,159] |
P00367 | Glutamate dehydrogenase 1 | GLUD1 | Energy metabolism (TCA cycle) | [141] |
P40926 | Malate dehydrogenase | MDH2 | Energy metabolism (TCA cycle) | [156,157,158,159] |
P20674 | Cytochrome c oxidase subunit 5a | COX5A | Energy metabolism (ETC) | [159] |
P09622 | Dihydrolipoyl dehydrogenase | DLD | Energy metabolism (ETC) | [151] |
O75489 | NADH dehydrogenase (ubiquinone) iron-sulfur protein 3 | NDUFS3 | Energy metabolism (ETC) | [159] |
P31930 | Ubiquinol-cytochrome c reductase complex core protein 1 | UQCRC1 | Energy metabolism (ETC) | [141] |
P25705 | ATP synthase subunit alpha | ATP5F1A | Energy metabolism (OxPhos) | [137,151,155,156,157,158,159,160] |
P06576 | ATP synthase subunit beta | ATP5F1B | Energy metabolism (OxPhos) | [137,141,160] |
O75947 | ATP synthase subunit d | ATP5H | Energy metabolism (OxPhos) | [159] |
P48047 | ATP synthase subunit o | ATP5PO | Energy metabolism (OxPhos) | [159] |
P12532 | Creatine Kinase U-type | CKMT1A | Energy metabolism (energy transduction) | [159] |
P15104 | Glutamine synthetase | GLUL | Neurotransmission | [141,156,157,158,159] |
P49411 | Elongation factor Tu | TUFM | Proteostasis | [156,157,158,159] |
P10809 | Heat shock protein 60KDa | HSPD1 | Proteostasis | [141,151,159] |
Q99497 | Protein/nucleic acid deglycase DJ-1 | PARK7 | Proteostasis | [151] |
P04179 | Manganese superoxide dismutase | SOD2 | Antioxidants | [156,157,158,159] |
P21796 | Voltage-dependent anion-selective channel protein 1 | VDAC1 | Ion channel | [159] |
Aging | Alzheimer’s Disease |
---|---|
Minor loss of volume, thickness, and surface area | ↓↓ volume and thickness |
↑ neuron body size | Abnormalities in mitochondrial structure and dynamics |
↑ number of astrocytes | Mitochondrial-bioenergetic failure |
Minor changes in fatty acid profile | Loss-of-function of mitochondrial ATP synthase |
Minor changes of the phospholipid profile of mitochondrial and microsomal membranes: ↑ phosphatidycholine content, and ↓ phosphatidylethanolamine (PE) content (but increase PE molecular species containing DHA) | Alterations in lipid metabolism and lipidomic profile of neuronal membrane |
↑ lipoxidation-derived protein adducts | ↑↑ lipid peroxidation and lipoxidation-derived molecular damage |
↑ lipofuscin granule content | Expansion of molecular damage to components belonging to bioenergetics, neurotransmission, cytoskeleton, proteostasis, antioxidants, ion channel, and oxygen metabolism |
No changes in the expression of inflammatory mediators | Alterations of several mitochondrial activities (import of proteins, fusion and fission, mitophagy, cross-talk with other cell compartments) and gene expression |
No loss of neurons | Neuronal death |
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Jové, M.; Mota-Martorell, N.; Torres, P.; Ayala, V.; Portero-Otin, M.; Ferrer, I.; Pamplona, R. The Causal Role of Lipoxidative Damage in Mitochondrial Bioenergetic Dysfunction Linked to Alzheimer’s Disease Pathology. Life 2021, 11, 388. https://doi.org/10.3390/life11050388
Jové M, Mota-Martorell N, Torres P, Ayala V, Portero-Otin M, Ferrer I, Pamplona R. The Causal Role of Lipoxidative Damage in Mitochondrial Bioenergetic Dysfunction Linked to Alzheimer’s Disease Pathology. Life. 2021; 11(5):388. https://doi.org/10.3390/life11050388
Chicago/Turabian StyleJové, Mariona, Natàlia Mota-Martorell, Pascual Torres, Victoria Ayala, Manuel Portero-Otin, Isidro Ferrer, and Reinald Pamplona. 2021. "The Causal Role of Lipoxidative Damage in Mitochondrial Bioenergetic Dysfunction Linked to Alzheimer’s Disease Pathology" Life 11, no. 5: 388. https://doi.org/10.3390/life11050388