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Review
. 2024 Feb 2;13(2):191.
doi: 10.3390/antiox13020191.

CoQ10 and Mitochondrial Dysfunction in Alzheimer's Disease

Zdeněk Fišar  1 , Jana Hroudová  1
Affiliations
Review

CoQ10 and Mitochondrial Dysfunction in Alzheimer's Disease

Zdeněk Fišar et al. Antioxidants (Basel). .

Abstract

The progress in understanding the pathogenesis and treatment of Alzheimer's disease (AD) is based on the recognition of the primary causes of the disease, which can be deduced from the knowledge of risk factors and biomarkers measurable in the early stages of the disease. Insights into the risk factors and the time course of biomarker abnormalities point to a role for the connection of amyloid beta (Aβ) pathology, tau pathology, mitochondrial dysfunction, and oxidative stress in the onset and development of AD. Coenzyme Q10 (CoQ10) is a lipid antioxidant and electron transporter in the mitochondrial electron transport system. The availability and activity of CoQ10 is crucial for proper mitochondrial function and cellular bioenergetics. Based on the mitochondrial hypothesis of AD and the hypothesis of oxidative stress, the regulation of the efficiency of the oxidative phosphorylation system by means of CoQ10 can be considered promising in restoring the mitochondrial function impaired in AD, or in preventing the onset of mitochondrial dysfunction and the development of amyloid and tau pathology in AD. This review summarizes the knowledge on the pathophysiology of AD, in which CoQ10 may play a significant role, with the aim of evaluating the perspective of the pharmacotherapy of AD with CoQ10 and its analogues.

Keywords: Alzheimer’s disease; coenzyme Q10; drug; mitochondrial dysfunction; oxidative stress.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Biological hypotheses of Alzheimer’s disease. Solid arrow shows direct effect, dotted arrow shows indirect effect of coenzyme Q10 (CoQ10).
Figure 2
Figure 2
Simplified scheme of Alzheimer’s disease (AD) pathophysiology, with focus on the role of mitochondrial dysfunction. AD pathophysiology is associated with amyloid beta (Aβ) pathology (neurotoxicity of Aβ oligomers and plaques), tau pathology (neurotoxicity of tau oligomers and neurofibrillary tangles), mitochondrial dysfunction, oxidative stress, neuroinflammation, and loss of proteostasis. All these processes are interrelated and result in cellular and synaptic dysfunction, impaired neuroplasticity and neurochemistry, neurodegeneration (synaptic and neuronal loss and brain atrophy), cognitive decline, and AD dementia. Mitochondrial dysfunction associated with Aβ and tau pathology in AD includes decreased ATP production, mitophagy, biogenesis (peroxisome PGC-1α), activity of components of the OXPHOS system and other enzymes, mitochondrial membrane potential (Δψm), and import of mitochondrial proteins, imbalance of mitochondrial dynamics (DRP-1), impaired of intracellular Ca2+ homeostasis, membrane damage, interaction with ANT1 and VDAC1, and increased ROS production, apoptosis, and mPTP opening. Coenzyme Q10 (CoQ10), as a unique endogenous antioxidant and electron transporter in the OXPHOS system, may have a significant role in the pathophysiology and treatment of AD, primarily through the regulation of mitochondrial function. ANT1—adenine nucleotide translocator 1; ApoE4—apolipoprotein E4; APP—amyloid precursor protein; DRP-1—dynamin-like protein-1; HSD10—17β-hydroxysteroid dehydrogenase type 10; mPTP—mitochondrial permeability transition pore; NFTs—neurofibrillary tangles; OXPHOS—oxidative phosphorylation; PGC-1α—peroxisome proliferator-activated receptor gamma coactivator 1-alpha; P-tau—phosphorylated tau; ROS—reactive oxygen species; VDAC1—voltage-dependent anion channel 1.
Figure 3
Figure 3
Basic steps in coenzyme Q10 biosynthesis and three redox isoforms. HMG-CoA—β-Hydroxy β-methylglutaryl-coenzyme A.
Figure 4
Figure 4
A simplified diagram of the mitochondrial electron transport system (ETS) with electron transfer in the Q-cycle of complex III. Electrons enter the ETS via complex I or via complex II and are transferred by coenzyme Q10 (CoQ10) to complex III. CoQ10 can also transfer electrons from dehydrogenases (DH) located on the outer or inner surface of the inner mitochondrial membrane (IMM). In the Qo-site complex III near the outer side of the IMM, two electrons from one ubiquinol (CoQ10(H2)), and subsequently two more electrons from the second ubiquinol, pass into two bifurcated transfer chains: (1) The acceptor of the two electrons is the iron –sulfur cluster (Fe2S2 center) of the Rieske protein, which passes electrons via cytochrome c1 (cyt c1) to cytochrome c (cyt c) on the outer surface of the IMM. Cyt c transfers electrons to complex IV (cytochrome c oxidase), where oxygen is finally reduced to water. (2) The acceptor of the second two electrons in the Q-cycle is cytochrome b containing low (cyt bL) and high (cyt bH) potential hemes. This chain supplies electrons to the Qi-site at the matrix side of the IMM, where they reduce one ubiquinone (CoQ10) to semiquinone and then to ubiquinol. Complexes I and III (Qo-site) are the sources of superoxide (O2•–).
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