Mitochondrial Translocase of the Outer Membrane Alterations May Underlie Dysfunctional Oxidative Phosphorylation in Alzheimer’s Disease

Chai, Yuek Ling; Xing, Huayang; Chong, Jenny; Francis, Paul T.; Ballard, Clive; Chen, Christopher; Lai, Mitchell K.P.

doi:10.3233/jad-170613

Cited by 24 publications

(16 citation statements)

References 32 publications

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“…Gene set enrichment analysis of datasets from patients with AD archived in GeneNetwork showed disruption of mitochondrial import pathway as a hallmark of AD [40]. This was confirmed by investigation of protein expression in the brain tissue which revealed reduction of Tom20 and Tom70, as well as components of OXPHOS complex I and III in AD hippocampus [179].…”

Section: Impaired Mitochondrial Biogenesis In Admentioning

confidence: 70%

Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: recent advances

Wang

Zhao

et al. 2020

Mol Neurodegeneration

783

506

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Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases, characterized by impaired cognitive function due to progressive loss of neurons in the brain. Under the microscope, neuronal accumulation of abnormal tau proteins and amyloid plaques are two pathological hallmarks in affected brain regions. Although the detailed mechanism of the pathogenesis of AD is still elusive, a large body of evidence suggests that damaged mitochondria likely play fundamental roles in the pathogenesis of AD. It is believed that a healthy pool of mitochondria not only supports neuronal activity by providing enough energy supply and other related mitochondrial functions to neurons, but also guards neurons by minimizing mitochondrial related oxidative damage. In this regard, exploration of the multitude of mitochondrial mechanisms altered in the pathogenesis of AD constitutes novel promising therapeutic targets for the disease. In this review, we will summarize recent progress that underscores the essential role of mitochondria dysfunction in the pathogenesis of AD and discuss mechanisms underlying mitochondrial dysfunction with a focus on the loss of mitochondrial structural and functional integrity in AD including mitochondrial biogenesis and dynamics, axonal transport, ER-mitochondria interaction, mitophagy and mitochondrial proteostasis.

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Section: Impaired Mitochondrial Biogenesis In Admentioning

confidence: 70%

Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: recent advances

Wang

Zhao

et al. 2020

Mol Neurodegeneration

783

506

View full text Add to dashboard Cite

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“…In AD, the reduced immunoreactivity of TOMM20 was observed. The decreased levels of TOMM20 can lead to an impairment of the recognition and binding of proteins intended for translocation into mitochondria [527,528]. This could contribute to the damage of oxidative phosphorylation as seen in AD.…”

Section: Proteins Involved In the Regulation Of The Cytoskeleton And Intracellular Transportmentioning

confidence: 99%

Tau Protein Interaction Partners and Their Roles in Alzheimer’s Disease and Other Tauopathies

Sinsky

Pichlerova

Hanes

2021

IJMS

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Tau protein plays a critical role in the assembly, stabilization, and modulation of microtubules, which are important for the normal function of neurons and the brain. In diseased conditions, several pathological modifications of tau protein manifest. These changes lead to tau protein aggregation and the formation of paired helical filaments (PHF) and neurofibrillary tangles (NFT), which are common hallmarks of Alzheimer’s disease and other tauopathies. The accumulation of PHFs and NFTs results in impairment of physiological functions, apoptosis, and neuronal loss, which is reflected as cognitive impairment, and in the late stages of the disease, leads to death. The causes of this pathological transformation of tau protein haven’t been fully understood yet. In both physiological and pathological conditions, tau interacts with several proteins which maintain their proper function or can participate in their pathological modifications. Interaction partners of tau protein and associated molecular pathways can either initiate and drive the tau pathology or can act neuroprotective, by reducing pathological tau proteins or inflammation. In this review, we focus on the tau as a multifunctional protein and its known interacting partners active in regulations of different processes and the roles of these proteins in Alzheimer’s disease and tauopathies.

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“…Aberrant mitochondria are removed by a selective form of autophagy, termed mitophagy, which is a crucial mechanism in mitochondrial quality control [ 206 ]. Dysfunctional mitochondria and impaired mitophagy are observed in many pathological conditions and the mechanisms and implications of mitophagy were investigated in molecular detail particularly with respect to Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD) [ 207 , 208 , 209 ].…”

Section: Tom70 In Health and Diseasementioning

confidence: 99%

The Mitochondrial Outer Membrane Protein Tom70-Mediator in Protein Traffic, Membrane Contact Sites and Innate Immunity

Kreimendahl

Rassow

2020

IJMS

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Tom70 is a versatile adaptor protein of 70 kDa anchored in the outer membrane of mitochondria in metazoa, fungi and amoeba. The tertiary structure was resolved for the Tom70 of yeast, showing 26 α-helices, most of them participating in the formation of 11 tetratricopeptide repeat (TPR) motifs. Tom70 serves as a docking site for cytosolic chaperone proteins and co-chaperones and is thereby involved in the uptake of newly synthesized chaperone-bound proteins in mitochondrial biogenesis. In yeast, Tom70 additionally mediates ER-mitochondria contacts via binding to sterol transporter Lam6/Ltc1. In mammalian cells, TOM70 promotes endoplasmic reticulum (ER) to mitochondria Ca2+ transfer by association with the inositol-1,4,5-triphosphate receptor type 3 (IP3R3). TOM70 is specifically targeted by the Bcl-2-related protein MCL-1 that acts as an anti-apoptotic protein in macrophages infected by intracellular pathogens, but also in many cancer cells. By participating in the recruitment of PINK1 and the E3 ubiquitin ligase Parkin, TOM70 can be implicated in the development of Parkinson’s disease. TOM70 acts as receptor of the mitochondrial antiviral-signaling protein (MAVS) and thereby participates in the corresponding system of innate immunity against viral infections. The protein encoded by Orf9b in the genome of SARS-CoV-2 binds to TOM70, probably compromising the synthesis of type I interferons.

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Mitochondrial Translocase of the Outer Membrane Alterations May Underlie Dysfunctional Oxidative Phosphorylation in Alzheimer’s Disease

Cited by 24 publications

References 32 publications

Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: recent advances

Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: recent advances

Tau Protein Interaction Partners and Their Roles in Alzheimer’s Disease and Other Tauopathies

The Mitochondrial Outer Membrane Protein Tom70-Mediator in Protein Traffic, Membrane Contact Sites and Innate Immunity

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