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Review
. 2024 Aug 17;10(17):e36470.
doi: 10.1016/j.heliyon.2024.e36470. eCollection 2024 Sep 15.

Molecular mechanisms of mitochondrial homeostasis regulation in neurons and possible therapeutic approaches for Alzheimer's disease

Jiale Ren  1 , Beibei Xiang  1 , Lin Xueling  1 , Xiaolu Han  1 , Zhen Yang  1 , Mixia Zhang  1 , Yanjun Zhang  2
Affiliations
Review

Molecular mechanisms of mitochondrial homeostasis regulation in neurons and possible therapeutic approaches for Alzheimer's disease

Jiale Ren et al. Heliyon. .

Abstract

Alzheimer's disease (AD) is a neurological disease with memory loss and cognitive decline, which affects a large proportion of the aging population. Regrettably, there are no drug to reverse or cure AD and drug development for the primary theory of amyloid beta deposition has mostly failed. Therefore, there is an urgent need to investigate novel strategies for preventing AD. Recent studies demonstrate that imbalance of mitochondrial homeostasis is a driver in Aβ accumulation, which can lead to the occurrence and deterioration of cognitive impairment in AD patients. This suggests that regulating neuronal mitochondrial homeostasis may be a new strategy for AD. We summarize the importance of mitochondrial homeostasis in AD neuron and its regulatory mechanisms in this review. In addition, we summarize the results of studies indicating mitochondrial dysfunction in AD subjects, including impaired mitochondrial energy production, oxidative stress, imbalance of mitochondrial protein homeostasis, imbalance of fusion and fission, imbalance of neuronal mitochondrial biogenesis and autophagy, and altered mitochondrial motility, in hope of providing possible therapeutic approaches for AD.

Keywords: Alzheimer's disease; Mitochondrial dysfunction; Mitochondrial homeostasis; Neuronal apoptosis.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
The interaction of mitochondrial dysfunction with the pathology of Alzheimer's disease (AD), including amyloid beta plaque and tau deposition, contributes to neuronal dysfunction and apoptosis. While various factors have been identified as contributors to mitochondrial dysfunction, the correlation between AD pathology and neuronal apoptosis and dysfunction remains unclear.
Fig. 2
Fig. 2
Role of mitochondria in neurons, including buffering of Ca2+ homeostasis, providing neurons with energy, regulating neuronal excitability, synaptic plasticity and the generation and maturation of neurons. Mitochondria play a variety of key roles in neurons and are essential for maintaining normal function and homeostasis of neurons. IP3R: inositol 1,4,5-trisphosphate receptor. VDAC: voltage–dependent anion–selective channel. MCU: mitochondria calcium uniporter. TCA: Tricarboxylic acid cycle. NADH:Nicotinamide adenine dinucleotide. FADH2:Flavine adenine dinucleotide. ATP:Adenosine triphosphate. ADP:Adenosine diphosphate. CxI: reduced coenzyme I - ubiquinone oxidoreductase. CxII: succinate - ubiquinone oxidoreductase. Cx III: ubiquinol - cytochrome c oxidoreductase. Cx IV: cytochrome C oxidase.
Fig. 3
Fig. 3
Molecular mechanisms of mitochondrial homeostasis regulation in neurons. A. mitochondrial protein homeostasis regulation B. Molecular mechanisms of mitochondrial transport regulation C. Molecular mechanisms of mitochondrial biogenesis, mitophagy, fusion and fission regulation. OMM: outer mitochondrial membrane. IMS: intermembrane space. IMM: inner mitochondrial membrane. TOM:translocase of the outer membrane. TIM:translocase of the inner membrane. Miro: guanosine triphosphatase Rho GTPase. TRAK:Trafficking kinesin protein. KIF5: inesin heavy chain isoform 5. LC3: autophagosomal protein. OPTN: optineurin. NDP52: autophagy receptor proteins. Ub: ubiquitin. PINK1:PTEN-induced kinase 1. Parkin: E3 ubiquitin-protein ligase parkin. AMPK: Adenosine 5‘-monophosphate -activated protein kinase. SIRT1: silent mating-type information regulation 2 homolog 1. PGC-1α: Peroxisome proliferator-activated receptor gamma coactivator-1α. NRF1: Nuclear respiratory factor 1. NRF2: Nuclear respiratory factor 2. Mfn: mitofusin. OPA1: opticatrophy protein 1. Fis1: mitochondrial fission protein 1. Mff: mitochondrial fission factor. DRP1: dynamin-related protein 1. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
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