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Aging and disease
Orginal Article |
A Glimmer of Hope: Maintain Mitochondrial Homeostasis to Mitigate Alzheimer’s Disease
Wenbo Li1, Ling Kui2, Tsirukis Demetrios3, Xun Gong4, Min Tang5,6,*
1State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, China.
2Dana-Farber Cancer Institute, Harvard Medical School, United States
3Boston Children’s Hospital, Harvard Medical School, United States
4Department of Rheumatology & Immunology, The First Affiliated Hospital of Anhui Medical University, China
5Institute of Life Sciences, Jiangsu University, China
6Center for Innovation in Brain Science, University of Arizona, United States
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Abstract  

Mitochondria are classically known to be cellular energy producers. Given the high‐energy demanding nature of neurons in the brain, it is essential that the mitochondrial pool remains healthy and provides a continuous and efficient supply of energy. However, mitochondrial dysfunction is inevitable in aging and neurodegenerative diseases. In Alzheimer’s disease (AD), neurons experience unbalanced homeostasis like damaged mitochondrial biogenesis and defective mitophagy, with the latter promoting the disease-defining amyloid β (Aβ) and p-Tau pathologies impaired mitophagy contributes to inflammation and the aggregation of Aβ and p-Tau-containing neurotoxic proteins. Interventions that restore defective mitophagy may, therefore, alleviate AD symptoms, pointing out the possibility of a novel therapy. This review aims to illustrate mitochondrial biology with a focus on mitophagy and propose strategies to treat AD while maintaining mitochondrial homeostasis.

Keywords Alzheimer’s disease      mitochondria dysfunction      mitophagy      NAD+     
Corresponding Authors: Min Tang   
About author:

These authors contributed equally to this work.

Just Accepted Date: 10 January 2020  
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Wenbo Li
Ling Kui
Tsirukis Demetrios
Xun Gong
Min Tang
Cite this article:   
Wenbo Li,Ling Kui,Tsirukis Demetrios, et al. A Glimmer of Hope: Maintain Mitochondrial Homeostasis to Mitigate Alzheimer’s Disease[J]. Aging and disease, 10.14336/AD.2020.0105
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http://www.aginganddisease.org/EN/10.14336/AD.2020.0105     OR     http://www.aginganddisease.org/EN/Y/V/I/0
Figure 1.  Mitochondrial cell biology. (A) structure of mitochondrion and general features of mitochondrial dynamics (B) fusion (C) fission.
Figure 2.  Overview of autophagy/mitophagy in neurons.
PathwaysGenes/ProteinsRefs
The PINK1/Parkin-dependent pathwayPINK1, Parkin, USP8, USP30, AMBRA1, Bcl2, FUNDC1, MUL1, Nix, ATG5, LC3[74, 119]
The Parkin-independent pathwayPINK1[120]
The Reticulocyte pathwayNix, LC3[60]
The Zygote pathwayVCPs, MUL1, LC3[121-123]
The MDVs pathwayPINK1, Parkin, LC3[124]
The mTOR pathwayULK1, Atg1, Atg13, Akt, PKC, FOXO3[45]
Table 1  Summary of different pathways and genes/proteins involved in autophagy/mitophagy.
AgentsStudy modelEffectRefs
2,4-Dinitrophenol (DNP)animal modelstimulate autophagy[139]
rapamycinAD mousereduce Aβ pathology[45]
spermidinehuman and yeast cells; nematodesinduce autophagy independent of SIRT1[140]
urolithin AC. elegans; mouseinduce mitophagy, prolong lifespan; increase muscle function[141]
antibioticthe mt-Keima mouseprovide a method to analyze mitophagy alterations[81]
2-deoxyglucoseAD female mousestimulate ketogenesis and induce mild bioenergetic stress;
enhance mitochondrial function; stimulate autophagy and clearance of Aβ
[142-149]
nicotinamide mononucleotide (NMN)Mouse model of fatty liver disease; AD mouseincrease NAD+ pool[150-154]
5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)myopathy mouseactivates AMPK to acts on PGC-1[155-157]
actinoninCaenorhabditis elegansreverse memory impairment[77]
mdivi1excitotoxic mouseenhance DRP1 activity[158-164]
Table 2  Pharmacological agents potentially stimulate autophagy/mitophagy.
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