Mitochondrial complex I as a therapeutic target for Alzheimer's disease.
10.1016/j.apsb.2021.11.003
- Author:
Eugenia TRUSHINA
1
;
Sergey TRUSHIN
1
;
Md Fayad HASAN
1
Author Information
1. Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
- Publication Type:Review
- Keywords:
AD, Alzheimer's disease;
ADP, adenosine diphosphate;
AIDS, acquired immunodeficiency syndrome;
AMP, adenosine monophosphate;
AMPK, AMP-activated protein kinase;
APP/PS1, amyloid precursor protein/presenilin 1;
ATP, adenosine triphosphate;
Alzheimer's disease;
Aβ, amyloid beta;
BBB, blood‒brain barrier;
BDNF, brain-derived neurotrophic factor;
CP2, tricyclic pyrone compound two;
Complex I inhibitors;
ER, endoplasmic reticulum;
ETC, electron transport chain;
FADH2, flavin adenine dinucleotide;
FDG-PET, fluorodeoxyglucose-positron emission tomography;
GWAS, genome-wide association study;
HD, Huntington's disease;
HIF-1α, hypoxia induced factor 1 α;
Healthy aging;
ISR, integrated stress response;
Integrated stress response;
LTP, long term potentiation;
MCI, mild cognitive impairment;
MPTP, 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine;
Mitochondria;
Mitochondria signaling;
Mitochondria targeted therapeutics;
NAD+ and NADH, nicotinamide adenine dinucleotide;
NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells;
NRF2, nuclear factor E2-related factor 2;
Neuroprotection;
OXPHOS, oxidative phosphorylation;
PD, Parkinson's disease;
PGC1α, peroxisome proliferator-activated receptor gamma coactivator 1 alpha;
PMF, proton-motive force;
RNAi, RNA interference;
ROS, reactive oxygen species;
T2DM, type II diabetes mellitus;
TCA, the tricarboxylic acid cycle;
mtDNA, mitochondrial DNA;
mtUPR, mitochondrial unfolded protein response;
pTau, hyper-phosphorylated Tau protein;
ΔpH, proton gradient;
Δψm, mitochondrial membrane potential
- From:
Acta Pharmaceutica Sinica B
2022;12(2):483-495
- CountryChina
- Language:English
-
Abstract:
Alzheimer's disease (AD), the most prominent form of dementia in the elderly, has no cure. Strategies focused on the reduction of amyloid beta or hyperphosphorylated Tau protein have largely failed in clinical trials. Novel therapeutic targets and strategies are urgently needed. Emerging data suggest that in response to environmental stress, mitochondria initiate an integrated stress response (ISR) shown to be beneficial for healthy aging and neuroprotection. Here, we review data that implicate mitochondrial electron transport complexes involved in oxidative phosphorylation as a hub for small molecule-targeted therapeutics that could induce beneficial mitochondrial ISR. Specifically, partial inhibition of mitochondrial complex I has been exploited as a novel strategy for multiple human conditions, including AD, with several small molecules being tested in clinical trials. We discuss current understanding of the molecular mechanisms involved in this counterintuitive approach. Since this strategy has also been shown to enhance health and life span, the development of safe and efficacious complex I inhibitors could promote healthy aging, delaying the onset of age-related neurodegenerative diseases.
