Mitochondrial protein dysfunction in pathogenesis of neurological diseases

Wang, Liang; Zhou, Yang; He, X. T.; Pu, Shiming; Yang, Cheng; Wu, Qiong; Zhou, Zuping; Cen, Xiaobo; Zhao, Hongxia

doi:10.3389/fnmol.2022.974480

Cited by 20 publications

(10 citation statements)

References 573 publications

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“…5A ). Conversely, the depletion of GTPBP8 had no noticeable effect on the levels of long Opa1 (L-Opa1) and short Opa1 (S-Opa1), which are implicated in both mitochondrial fission and fusion ( Ishihara et al, 2006 ; Wang et al, 2022 ). This observation suggests that the influence of GTPBP8 depletion on the abundance of Drp1 is distinct and specific.…”

Section: Resultsmentioning

confidence: 98%

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GTPBP8 modulates mitochondrial fission through a Drp1-dependent process

He,

Wang,

Tsang

et al. 2024

Journal of Cell Science

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Mitochondrial fission is a tightly regulated process involving multiple proteins and cell signaling. Despite extensive studies on mitochondrial fission factors, our understanding of the regulatory mechanisms remains limited. This study shows the critical role of a mitochondrial GTPase, GTPBP8, in orchestrating mitochondrial fission. Depletion of GTPBP8 resulted in drastic elongation and interconnectedness of mitochondria. Conversely, overexpression of GTPBP8 shifted mitochondrial morphology from tubular to fragmented. Notably, the induced mitochondrial fragmentation from GTPBP8 overexpression was inhibited in cells either depleted of the mitochondrial fission protein Drp1 or carrying mutated forms of Drp1. Importantly, downregulation of GTPBP8 caused an increase in oxidative stress, modulating cell signaling involved in the heightened phosphorylation of Drp1 at Ser637. This phosphorylation hindered the recruitment of Drp1 to mitochondria, leading to mitochondrial fission defects. On the other hand, GTPBP8 overexpression triggered enhanced recruitment and assembly of Drp1 to mitochondria. In summary, our study illuminates the cellular function of GTPBP8 as a pivotal modulator of the mitochondrial division apparatus, inherently reliant on its influence on Drp1.

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Section: Resultsmentioning

confidence: 98%

“…Mitochondrial fission is dependent on Drp1, which assembles into helical oligomers, enveloping the pre-constriction site to facilitate membrane constriction ( Wang et al, 2022 ). To investigate whether the decreased mitochondrial fission upon GTPBP8 depletion was correlated with Drp1 abundance, the expression level of Drp1 was assessed.…”

Section: Resultsmentioning

confidence: 99%

GTPBP8 modulates mitochondrial fission through a Drp1-dependent process

He,

Wang,

Tsang

et al. 2024

Journal of Cell Science

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“…Mitochondria dysfunction has been repeatedly reported in heart diseases and neurological disorders ( 40 – 45 ), but the underlying mechanisms are still not fully understood ( 43 , 46 – 50 ). In this study, our established heart-specific KO Atp8 ( Atp8 MHC-Cre ) and Nd1 ( Nd1 MHC-Cre ) rats displayed growth retardation, short life span, dilated cardiomyopathy, and impaired mitochondria structure.…”

Section: Discussionmentioning

confidence: 99%

A conditional knockout rat resource of mitochondrial protein-coding genes via a DdCBE-induced premature stop codon

Tan

Kong

et al. 2023

Sci. Adv.

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Hundreds of pathogenic variants of mitochondrial DNA (mtDNA) have been reported to cause mitochondrial diseases, which still lack effective treatments. It is a huge challenge to install these mutations one by one. We repurposed the DddA-derived cytosine base editor to incorporate a premature stop codon in the mtProtein-coding genes to ablate mitochondrial proteins encoded in the mtDNA (mtProteins) instead of installing pathogenic variants and generated a library of both cell and rat resources with mtProtein depletion. In vitro, we depleted 12 of 13 mtProtein-coding genes with high efficiency and specificity, resulting in decreased mtProtein levels and impaired oxidative phosphorylation. Moreover, we generated six conditional knockout rat strains to ablate mtProteins using Cre/loxP system . Mitochondrially encoded ATP synthase membrane subunit 8 and NADH:ubiquinone oxidoreductase core subunit 1 were specifically depleted in heart cells or neurons, resulting in heart failure or abnormal brain development. Our work provides cell and rat resources for studying the function of mtProtein-coding genes and therapeutic strategies.

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“…Mitophagy, which is the process of removing damaged mitochondria is impaired during pathological conditions [ 7 ]. Deregulation of MQC processes and ultimately mitochondrial dysfunction has been implicated in sarcopenia [ 16 ], glaucoma [ 17 ], lung disease [ 18 ], infection, obesity, type 2 diabetes/diabetes kidney disease [ 19 ], hepatic ischemia-reperfusion injury [ 20 ], cardiovascular disease [ 21 ], neurological diseases [ 22 ] and age-related diseases [ 9 , 23 ].…”

Section: Mitochondrial Dysfunction and Diseasementioning

confidence: 99%

Effects of carotenoids on mitochondrial dysfunction

Ademowo,

Oyebode,

Edward

et al. 2024

Biochemical Society Transactions

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Oxidative stress, an imbalance between pro-oxidant and antioxidant status, favouring the pro-oxidant state is a result of increased production of reactive oxygen species (ROS) or inadequate antioxidant protection. ROS are produced through several mechanisms in cells including during mitochondrial oxidative phosphorylation. Increased mitochondrial-derived ROS are associated with mitochondrial dysfunction, an early event in age-related diseases such as Alzheimer's diseases (ADs) and in metabolic disorders including diabetes. AD post-mortem investigations of affected brain regions have shown the accumulation of oxidative damage to macromolecules, and oxidative stress has been considered an important contributor to disease pathology. An increase in oxidative stress, which leads to increased levels of superoxide, hydrogen peroxide and other ROS in a potentially vicious cycle is both causative and a consequence of mitochondrial dysfunction. Mitochondrial dysfunction may be ameliorated by molecules with antioxidant capacities that accumulate in mitochondria such as carotenoids. However, the role of carotenoids in mitigating mitochondrial dysfunction is not fully understood. A better understanding of the role of antioxidants in mitochondrial function is a promising lead towards the development of novel and effective treatment strategies for age-related diseases. This review evaluates and summarises some of the latest developments and insights into the effects of carotenoids on mitochondrial dysfunction with a focus on the antioxidant properties of carotenoids. The mitochondria-protective role of carotenoids may be key in therapeutic strategies and targeting the mitochondria ROS is emerging in drug development for age-related diseases.

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Mitochondrial protein dysfunction in pathogenesis of neurological diseases

Cited by 20 publications

References 573 publications

GTPBP8 modulates mitochondrial fission through a Drp1-dependent process

GTPBP8 modulates mitochondrial fission through a Drp1-dependent process

A conditional knockout rat resource of mitochondrial protein-coding genes via a DdCBE-induced premature stop codon

Effects of carotenoids on mitochondrial dysfunction

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