Influence of metformin on mitochondrial subproteome in the brain of apoE knockout mice

Suski, Maciej; Olszanecki, Rafał; Chmura, Łukasz; Stachowicz, Aneta; Madej, Józef; Okoń, Krzysztof; Adamek, Dariusz; Korbut, Ryszard

doi:10.1016/j.ejphar.2015.12.036

Cited by 10 publications

(4 citation statements)

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“…Metformin treatment of animal models of nonalcoholic fatty liver disease has revealed differential expression of mitochondrial proteins, especially those related to metabolism, oxidative stress, and respiration [ 34 ]. Furthermore, mitochondrial subproteome analysis of mouse brains [ 35 ] has identified differential expression of proteins involved in metabolic processes, apoptosis, and mitochondria structure. Whole brain phosphoproteomic assessment has also suggested that mitochondrial proteins and proteins functioning in metabolism are altered [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Activation of the ATF2/CREB-PGC-1α pathway by metformin leads to dopaminergic neuroprotection

et al. 2017

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Progressive dopaminergic neurodegeneration is responsible for the canonical motor deficits in Parkinson's disease (PD). The widely prescribed anti-diabetic medicine metformin is effective in preventing neurodegeneration in animal models; however, despite the significant potential of metformin for treating PD, the therapeutic effects and molecular mechanisms underlying dopaminergic neuroprotection by metformin are largely unknown.In this study, we found that metformin induced substantial proteomic changes, especially in metabolic and mitochondrial pathways in the substantia nigra (SN). Consistent with this data, metformin increased mitochondrial marker proteins in SH-SY5Y neuroblastoma cells. Mitochondrial protein expression by metformin was found to be brain region specific, with metformin increasing mitochondrial proteins in the SN and the striatum, but not the cortex. As a potential upstream regulator of mitochondria gene transcription by metformin, PGC-1α promoter activity was stimulated by metformin via CREB and ATF2 pathways. PGC-1α and phosphorylation of ATF2 and CREB by metformin were selectively increased in the SN and the striatum, but not the cortex. Finally, we showed that metformin protected dopaminergic neurons and improved dopamine-sensitive motor performance in an MPTP-induced PD animal model. Together these results suggest that the metformin-ATF2/CREB-PGC-1α pathway might be promising therapeutic target for PD.

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Section: Discussionmentioning

confidence: 99%

Activation of the ATF2/CREB-PGC-1α pathway by metformin leads to dopaminergic neuroprotection

et al. 2017

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“…ApoE knockout mice have been used as a model of AD as they exhibit mild neurodegenerative changes and behavioural abnormalities relevant to the early stages of this disorder, including synaptic and dendrite loss, lipid peroxidation, cellular stress, behavioural alterations in Morris water maze test and deficits in long-term potentiation (LTP) [26–30]. We used this mouse model to study whether chronic low-dose-rate radiation could be a potential risk factor in AD aetiology.…”

Section: Discussionmentioning

confidence: 99%

Chronic low-dose-rate ionising radiation affects the hippocampal phosphoproteome in the ApoE−/− Alzheimer's mouse model

et al. 2016

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Accruing data indicate that radiation-induced consequences resemble pathologies of neurodegenerative diseases such as Alzheimer's. The aim of this study was to elucidate the effect on hippocampus of chronic low-dose-rate radiation exposure (1 mGy/day or 20 mGy/day) given over 300 days with cumulative doses of 0.3 Gy and 6.0 Gy, respectively. ApoE deficient mutant C57Bl/6 mouse was used as an Alzheimer's model. Using mass spectrometry, a marked alteration in the phosphoproteome was found at both dose rates. The radiation-induced changes in the phosphoproteome were associated with the control of synaptic plasticity, calcium-dependent signalling and brain metabolism. An inhibition of CREB signalling was found at both dose rates whereas Rac1-Cofilin signalling was found activated only at the lower dose rate. Similarly, the reduction in the number of activated microglia in the molecular layer of hippocampus that paralleled with reduced levels of TNFα expression and lipid peroxidation was significant only at the lower dose rate. Adult neurogenesis, investigated by Ki67, GFAP and NeuN staining, and cell death (activated caspase-3) were not influenced at any dose or dose rate. This study shows that several molecular targets induced by chronic low-dose-rate radiation overlap with those of Alzheimer's pathology. It may suggest that ionising radiation functions as a contributing risk factor to this neurodegenerative disease.

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“…A metformin pro-survival effect also involves its influence on mitochondrial biogenesis; for example, it was shown that metformin inhibited mitochondrial damage via an AMP-activated protein kinase-dependent pathway in neuronal cells [14,15]. Due to the fact that the functional and structural mitochondrial defects contribute to the pathogenesis of neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease, it seems that metformin could ameliorate the plasticity of neuronal cells by modulating mitochondrial biogenesis and affecting the clearance of mitochondrial reactive oxygen species (ROS) [16,17]. Cellular ROS production is a common hallmark of apoptosis and senescence processes [18].…”

Section: Introductionmentioning

confidence: 99%

Antioxidant and Anti-Senescence Effect of Metformin on Mouse Olfactory Ensheathing Cells (mOECs) May Be Associated with Increased Brain-Derived Neurotrophic Factor Levels—An Ex Vivo Study

Śmieszek

Stręk

Kornicka

et al. 2017

IJMS

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Metformin, the popular anti-diabetic drug was shown to exert multiple biological effects. The most recent metformin gained attention as an agent that mobilizes endogenous progenitor cells and enhances regenerative potential of organisms, for example by promoting neurogenesis. In the present study, we examined the role of metformin on mouse olfactory ensheathing cells (mOECs) derived from animals receiving metformin for eight weeks at a concentration equal to 2.8 mg/day. The mOECs expanded ex vivo were characterized in terms of their cellular phenotype, morphology, proliferative activity, viability and accumulation of oxidative stress factors. Moreover, we determined the mRNA and protein levels of brain-derived neurotrophic factor (BDNF), distinguishing the secretion of BDNF by mOECs in cultures and circulating serum levels of BDNF. The mOECs used in the experiment were glial fibrillary acidic protein (GFAP) and p75 neurotrophin receptor (p75NTR) positive and exhibited both astrocyte-like and non-myelin Schwann cell-like morphologies. Our results revealed that the proliferation of OECs derived from mice treated with metformin was lowered, when compared to control group. Simultaneously, we noted increased cell viability, reduced expression of markers associated with cellular senescence and a decreased amount of reactive oxygen species. We observed increased mRNA expression of BDNF and its down-stream genes. Obtained results indicate that metformin may exert antioxidant, anti-apoptotic and senolytic action on OECs expanded ex vivo.

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Influence of metformin on mitochondrial subproteome in the brain of apoE knockout mice

Cited by 10 publications

References 71 publications

Activation of the ATF2/CREB-PGC-1α pathway by metformin leads to dopaminergic neuroprotection

Activation of the ATF2/CREB-PGC-1α pathway by metformin leads to dopaminergic neuroprotection

Chronic low-dose-rate ionising radiation affects the hippocampal phosphoproteome in the ApoE−/− Alzheimer's mouse model

Antioxidant and Anti-Senescence Effect of Metformin on Mouse Olfactory Ensheathing Cells (mOECs) May Be Associated with Increased Brain-Derived Neurotrophic Factor Levels—An Ex Vivo Study

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