Modulation of OSCP mitigates mitochondrial and synaptic deficits in a mouse model of Alzheimer's pathology

Gauba, Esha; Sui, Shaomei; Tian, Jing; Driskill, Christopher; Jia, Kun; Yu, Chunxiao; Rughwani, Tripta; Wang, Qi; Kroener, Sven; Guo, Lan; Du, Heng

doi:10.1016/j.neurobiolaging.2020.09.018

Cited by 7 publications

(4 citation statements)

References 61 publications

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“…Another promising target for mPTP regulation is OSCP. One of our recent studies confirmed a protective effect of OSCP restoration against neuronal mPTP activation and synaptic injury in an Aβ-based AD mouse model in vivo [131]. In this scenario, manipulation of OSCP through gene therapy gives hope for a future therapy for AD that needs validation by further clinical trials.…”

Section: Mptp As a Therapeutic Target For Admentioning

confidence: 56%

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Mitochondrial Permeability Transition: A Pore Intertwines Brain Aging and Alzheimer’s Disease

Jia

2021

Cells

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Advanced age is the greatest risk factor for aging-related brain disorders including Alzheimer’s disease (AD). However, the detailed mechanisms that mechanistically link aging and AD remain elusive. In recent years, a mitochondrial hypothesis of brain aging and AD has been accentuated. Mitochondrial permeability transition pore (mPTP) is a mitochondrial response to intramitochondrial and intracellular stresses. mPTP overactivation has been implicated in mitochondrial dysfunction in aging and AD brains. This review summarizes the up-to-date progress in the study of mPTP in aging and AD and attempts to establish a link between brain aging and AD from a perspective of mPTP-mediated mitochondrial dysfunction.

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Section: Mptp As a Therapeutic Target For Admentioning

confidence: 56%

“…Of note, in addition to extracellular deposition of Aβ, intracellular Aβ accumulation is a feature of AD neurons [130]. Previous studies highlighted the mitochondrial toxicity of intra-mitochondrial Aβ [22,36,[131][132][133]. However, the precise pathways for Aβ's entry into mitochondria remain unresolved so far.…”

Section: Mptp In Admentioning

confidence: 99%

Mitochondrial Permeability Transition: A Pore Intertwines Brain Aging and Alzheimer’s Disease

Jia

2021

Cells

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“… 191 Moreover, restored mitochondrial bioenergetics enhanced cognition in an AD (5xFAD) mouse model by blocking the deleterious impact of CypD on OSCP or by overexpressing OSCP. 192 , 193 Increased binding among Aβ, the apoE4 fragment, Tau and respiratory chain proteins leads to mitochondrial dysfunction. 194 , 195 Complex I activity was disrupted during OXPHOS by Ndufs2 deletion and caused human-like PD in mice.…”

Section: Mitochondrial Heterogeneity Under Pathological Conditionsmentioning

confidence: 99%

Mitochondrial heterogeneity in diseases

Chen,

Zhou,

et al. 2023

Sig Transduct Target Ther

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As key organelles involved in cellular metabolism, mitochondria frequently undergo adaptive changes in morphology, components and functions in response to various environmental stresses and cellular demands. Previous studies of mitochondria research have gradually evolved, from focusing on morphological change analysis to systematic multiomics, thereby revealing the mitochondrial variation between cells or within the mitochondrial population within a single cell. The phenomenon of mitochondrial variation features is defined as mitochondrial heterogeneity. Moreover, mitochondrial heterogeneity has been reported to influence a variety of physiological processes, including tissue homeostasis, tissue repair, immunoregulation, and tumor progression. Here, we comprehensively review the mitochondrial heterogeneity in different tissues under pathological states, involving variant features of mitochondrial DNA, RNA, protein and lipid components. Then, the mechanisms that contribute to mitochondrial heterogeneity are also summarized, such as the mutation of the mitochondrial genome and the import of mitochondrial proteins that result in the heterogeneity of mitochondrial DNA and protein components. Additionally, multiple perspectives are investigated to better comprehend the mysteries of mitochondrial heterogeneity between cells. Finally, we summarize the prospective mitochondrial heterogeneity-targeting therapies in terms of alleviating mitochondrial oxidative damage, reducing mitochondrial carbon stress and enhancing mitochondrial biogenesis to relieve various pathological conditions. The possibility of recent technological advances in targeted mitochondrial gene editing is also discussed.

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“…As mentioned in this review, several studies have demonstrated the presence of mitochondrial dysfunction in the brains of AD patients [ 76 , 276 – 278 ] and that this could be associated with the impairment of synaptic transmission and cognitive decline present during this disease [ 279 , 280 ]. Furthermore, as was described before, abnormal mitochondrial dynamics, bioenergetics impairment, and oxidative damage are observed in AD [ 20 , 93 , 102 ].…”

Section: Mitochondrial Dysfunction In Fibroblasts Obtained From Ad Pd...mentioning

confidence: 99%

The use of fibroblasts as a valuable strategy for studying mitochondrial impairment in neurological disorders

Olesen

Villavicencio-Tejo

Quintanilla

2022

Transl Neurodegener

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Neurological disorders (NDs) are characterized by progressive neuronal dysfunction leading to synaptic failure, cognitive impairment, and motor injury. Among these diseases, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS) have raised a significant research interest. These disorders present common neuropathological signs, including neuronal dysfunction, protein accumulation, oxidative damage, and mitochondrial abnormalities. In this context, mitochondrial impairment is characterized by a deficiency in ATP production, excessive production of reactive oxygen species, calcium dysregulation, mitochondrial transport failure, and mitochondrial dynamics deficiencies. These defects in mitochondrial health could compromise the synaptic process, leading to early cognitive dysfunction observed in these NDs. Interestingly, skin fibroblasts from AD, PD, HD, and ALS patients have been suggested as a useful strategy to investigate and detect early mitochondrial abnormalities in these NDs. In this context, fibroblasts are considered a viable model for studying neurodegenerative changes due to their metabolic and biochemical relationships with neurons. Also, studies of our group and others have shown impairment of mitochondrial bioenergetics in fibroblasts from patients diagnosed with sporadic and genetic forms of AD, PD, HD, and ALS. Interestingly, these mitochondrial abnormalities have been observed in the brain tissues of patients suffering from the same pathologies. Therefore, fibroblasts represent a novel strategy to study the genesis and progression of mitochondrial dysfunction in AD, PD, HD, and ALS. This review discusses recent evidence that proposes fibroblasts as a potential target to study mitochondrial bioenergetics impairment in neurological disorders and consequently to search for new biomarkers of neurodegeneration.

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Modulation of OSCP mitigates mitochondrial and synaptic deficits in a mouse model of Alzheimer's pathology

Cited by 7 publications

References 61 publications

Mitochondrial Permeability Transition: A Pore Intertwines Brain Aging and Alzheimer’s Disease

Mitochondrial Permeability Transition: A Pore Intertwines Brain Aging and Alzheimer’s Disease

Mitochondrial heterogeneity in diseases

The use of fibroblasts as a valuable strategy for studying mitochondrial impairment in neurological disorders

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