Mitochondrial complex I as a therapeutic target for Alzheimer's disease

Trushina, Eugenia; Trushin, Sergey; Hasan, Fayad

doi:10.1016/j.apsb.2021.11.003

Cited by 59 publications

(42 citation statements)

References 151 publications

(186 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Here in this study, we showed the neuroprotective role of UBA52 through its participation in maintenance of redox balance, mitochondrial functions, and neuronal viability. Mitochondrial dysfunction particularly the impairment of complex-I activity has been implicated in PD pathology since nineties [3] and recently been reported to be as therapeutic target for AD [48]. The present study was focused on the pathogenesis of PD-specific dopaminergic neurons employing rotenone induced experimental PD model which is of great interest and mimic most of the PD pathology specific mechanistic events [42,49,50].…”

Section: Discussionmentioning

confidence: 99%

UBA52 attunes VDAC1-mediated mitochondrial dysfunction and dopaminergic neuronal death

Tiwari

Singh

Gupta

et al. 2022

Preprint

View full text Add to dashboard Cite

Mitochondrial homeostasis regulates energy metabolism, calcium buffering, cell function and apoptosis. The present study has been conducted to investigate the implications of ubiquitin-encoding gene UBA52 in mitochondrial physiology. Transient expression of Myc-UBA52 in neurons significantly inhibited the rotenone-induced increase in reactive oxygen species generation, nitrite level and depleted glutathione level. Mass spectrometric and co-immunoprecipitation data suggested the profound interaction of UBA52 with mitochondrial outer membrane channel protein, VDAC1 in both the wild-type and Myc-alpha-synuclein overexpressed neuronal cells and in the Parkinson disease (PD)-specific substantia nigra and striatal region of the rat brain. In vitro ubiquitylation assay revealed that UBA52 participates in the ubiquitylation of VDAC1 through E3 ligase CHIP. Myc-UBA52 overexpression in neurons further improved the mitochondrial functionality and cell viability by preventing the alteration in mitochondrial membrane potential, mitochondrial complex-I activity, translocation of cytochrome-c and p-Nrf2 along with effect on intracellular calcium uptake, thus collectively inhibiting the opening of mitochondrial permeability transition pore. Additionally, Myc-UBA52 expression in neuronal cells offered protection against apoptotic and autophagic cell death. Altogether, our findings delineate functional association between UBA52 and mitochondrial homeostasis, providing new insights into the deterrence of dopaminergic cell death during acute PD pathogenesis.

show abstract

Section: Discussionmentioning

confidence: 99%

UBA52 attunes VDAC1-mediated mitochondrial dysfunction and dopaminergic neuronal death

Tiwari

Singh

Gupta

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…In a very recent and interesting review study [144], data are collected regarding mitochondrial complexes of ETC involved in OXPHOS which can function as a hub for small molecule-targeted therapeutics that provide improved mitochondrial activity and increased cellular energy are collected. Notably, the partial inhibition of the mitochondrial complex I (CI, NADH: ubiquinone oxidoreductase) with small molecules, i.e., metformin (MET), resveratrol (RSV), berberine and epigallocatechin-3-gallate (EGCG), has emerged as a therapeutic strategy for multiple human conditions, such as cancer and neurodegenerative diseases, including AD [144]. In detail, all four CI inhibitors have been observed to penetrate the BBB, although their pharmacological properties and bioavailability need to be improved in order to increase therapeutic efficacy.…”

Section: Therapeutic Strategies Targeting Mitochondrial Bioenergeticsmentioning

confidence: 99%

“…In detail, all four CI inhibitors have been observed to penetrate the BBB, although their pharmacological properties and bioavailability need to be improved in order to increase therapeutic efficacy. In fact, the therapeutic action of RSV, berberine and EGCG turns out to be limited, possibly due to poor stability, short half-life and very low bioavailability (<1%), in contrast to MET [144].…”

Section: Therapeutic Strategies Targeting Mitochondrial Bioenergeticsmentioning

confidence: 99%

Therapeutic Potential of Targeting Mitochondria for Alzheimer’s Disease Treatment

Atlante

Amadoro

Latina

et al. 2022

JCM

View full text Add to dashboard Cite

Alzheimer’s disease (AD), a chronic and progressive neurodegenerative disease, is characterized by memory and cognitive impairment and by the accumulation in the brain of abnormal proteins, more precisely beta-amyloid (β-amyloid or Aβ) and Tau proteins. Studies aimed at researching pharmacological treatments against AD have focused precisely on molecules capable, in one way or another, of preventing/eliminating the accumulations of the aforementioned proteins. Unfortunately, more than 100 years after the discovery of the disease, there is still no effective therapy in modifying the biology behind AD and nipping the disease in the bud. This state of affairs has made neuroscientists suspicious, so much so that for several years the idea has gained ground that AD is not a direct neuropathological consequence taking place downstream of the deposition of the two toxic proteins, but rather a multifactorial disease, including mitochondrial dysfunction as an early event in the pathogenesis of AD, occurring even before clinical symptoms. This is the reason why the search for pharmacological agents capable of normalizing the functioning of these subcellular organelles of vital importance for nerve cells is certainly to be considered a promising approach to the design of effective neuroprotective drugs aimed at preserving this organelle to arrest or delay the progression of the disease. Here, our intent is to provide an updated overview of the mitochondrial alterations related to this disorder and of the therapeutic strategies (both natural and synthetic) targeting mitochondrial dysfunction.

show abstract

“…Mitochondria are highly dynamic organelles whose morphology, distribution and activity depend on fusion and fission ( Chan, 2017 ). Several neurodegenerative diseases, such as optic atrophy, Charcot-Marie-Tooth disease, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, are associated with altered mitochondrial dynamics ( Cisneros et al, 2022 ; Li et al, 2022 ; Trushina et al, 2022 ). The prevalence of mitochondrial diseases is approximately 1:2,000, and with recent advances in identification mitochondria DNA, mitochondrial proteins and genetic diagnostics, the number of disease-related variantss in humans is expected to increase substantially ( Suomalainen, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Case Report: Evidences of myasthenia and cerebellar atrophy in a chinese patient with novel compound heterozygous MSTO1 variants

Liu

Huang

et al. 2022

Front. Genet.

View full text Add to dashboard Cite

Misato Mitochondrial Distribution and Morphology Regulator 1 (MSTO1) is a soluble cytoplasmic protein that regulates mitochondrial dynamics by promoting mitochondrial fusion. Variants in the MSTO1 gene cause a rare disease characterized by early-onset myopathy and cerebellar ataxia, with almost 30 cases reported worldwide. Here we report a case of a 3-year-old boy with novel heterozygous variants of the MSTO1 gene (c.1A>G (p.M1?) and c.727G>C(p.Ala243Pro)). Sequencing data and subsequent validation show that the two variants were inherited from the mother and father of the patient (both were heterozygous). The clinical features are infancy-onset mental and motor retardation, language disorder, dysarthria, scoliosis, cerebellar atrophy, tremor, lower-extremity muscle weakness, elevated muscle enzymes, extensive myopathy with chronic atrophy, hyperventilation lungs, and previously unreported hairy back and enlarged gastrocnemius. Finally, novel heterozygous MSTO1 variants were discovered in this case, which expands the gene spectrum and clinical phenotype of this type of disease, and provides a new direction for future treatment and research. Then we summarize the mutational spectrum, pathological, clinical features and imaging of MSTO1 variants in a cohort of reported 31 patients and discuss the pathogenesis of MSTO1 in humans.

show abstract

Mitochondrial complex I as a therapeutic target for Alzheimer's disease

Cited by 59 publications

References 151 publications

UBA52 attunes VDAC1-mediated mitochondrial dysfunction and dopaminergic neuronal death

UBA52 attunes VDAC1-mediated mitochondrial dysfunction and dopaminergic neuronal death

Therapeutic Potential of Targeting Mitochondria for Alzheimer’s Disease Treatment

Case Report: Evidences of myasthenia and cerebellar atrophy in a chinese patient with novel compound heterozygous MSTO1 variants

Contact Info

Product

Resources

About