MicroRNA-7 Promotes Glycolysis to Protect against 1-Methyl-4-phenylpyridinium-induced Cell Death

Chaudhuri, Amrita Datta; Kabaria, Savan; Choi, Doo Chul; Mouradian, M. Maral; Junn, Eunsung

doi:10.1074/jbc.m114.625962

Cited by 57 publications

(50 citation statements)

References 36 publications

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“…Furthermore, inhibition of GLUT-like transporters with STF-31 or AA (a competitive inhibitor for GLUT-like transport of glucose) also protected against PQ toxicity (Figure 8b). It has also been reported that upregulation of GLUT3 protects against MPP + -induced toxicity, 74 which agrees with our observation that while inhibition of glucose metabolism significantly reduces PQ toxicity, it stimulates dopaminergic cell death induced by MPP + . SGLT6 and GLUT8 (and probably GLUT4) seem to be the glucose transporters primarily found in the substantia nigra.…”

Section: Discussionsupporting

confidence: 93%

Glucose Metabolism and AMPK Signaling Regulate Dopaminergic Cell Death Induced by Gene (α-Synuclein)-Environment (Paraquat) Interactions

et al. 2016

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While environmental exposures are not the single cause of Parkinson’s disease (PD), their interaction with genetic alterations is thought to contribute to neuronal dopaminergic degeneration. However, the mechanisms involved in dopaminergic cell death induced by gene-environment interactions remain unclear. In this work, we have revealed for the first time the role of central carbon metabolism and metabolic dysfunction in dopaminergic cell death induced by paraquat (PQ)-α-synuclein interaction. The toxicity of PQ in dopaminergic N27 cells was significantly reduced by glucose deprivation, inhibition of hexokinase with 2-deoxy-D-glucose (2-DG), or equimolar substitution of glucose with galactose, which evidenced the contribution of glucose metabolism to PQ-induced cell death. PQ also stimulated an increase in glucose uptake, and the translocation of glucose transporter type 4 (GLUT4) and Na+-glucose transporters isoform 1 (SGLT1) proteins to the plasma membrane, but only inhibition of GLUT-like transport with STF-31 or ascorbic acid reduced PQ-induced cell death. Importantly, while autophagy protein 5 (ATG5)/unc-51 like autophagy activating kinase 1 (ULK1)-dependent autophagy protected against PQ toxicity, the inhibitory effect of glucose deprivation on cell death progression was largely independent of autophagy or mammalian target of rapamycin (mTOR) signaling. PQ selectively induced metabolomic alterations and adenosine monophosphate-activated protein kinase (AMPK) activation in the midbrain and striatum of mice chronically treated with PQ. Inhibition of AMPK signaling led to metabolic dysfunction and an enhanced sensitivity of dopaminergic cells to PQ. In addition, activation of AMPK by PQ was prevented by inhibition of the inducible nitric oxide syntase (iNOS) with 1400W, but PQ had no effect on iNOS levels. Overexpression of wild type or A53T mutant α-synuclein stimulated glucose uptake and PQ toxicity, and this toxic synergism was reduced by inhibition of glucose metabolism/transport and the pentose phosphate pathway (6-aminonicotinamide). These results demonstrate that glucose metabolism and AMPK regulate dopaminergic cell death induced by gene (α-synuclein)-environment (PQ) interactions.

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Section: Discussionsupporting

confidence: 93%

Glucose Metabolism and AMPK Signaling Regulate Dopaminergic Cell Death Induced by Gene (α-Synuclein)-Environment (Paraquat) Interactions

et al. 2016

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“…In previous studies, we have also demonstrated that miR-7 attenuates neurotoxic effects of MPP ϩ by down-regulating RelA, which belongs to the nuclear factor B (NF-B) family of transcription factors (17,18). In the absence of any stimulus, RelA is sequestered in the cytosol by a protein, inhibitor of B (IB).…”

Section: Discussionmentioning

confidence: 99%

“…miR-7 could functionally target 3Ј-UTR of ␣-synuclein mRNA, resulting in decrease in its mRNA and protein levels, which could potentially help to prevent aggregation of ␣-synuclein, a prominent feature of PD pathology (15,16). In addition, miR-7 has been shown to protect neuronal cells against the cytotoxic effect of MPP ϩ by down-regulating another target, RelA, through promoting glycolysis (17,18).…”

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confidence: 99%

MicroRNA-7 Regulates the Function of Mitochondrial Permeability Transition Pore by Targeting VDAC1 Expression

Chaudhuri

Choi

Kabaria

et al. 2016

Journal of Biological Chemistry

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106

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Mitochondrial dysfunction is one of the major contributors to neurodegenerative disorders including Parkinson disease. The mitochondrial permeability transition pore is a protein complex located on the mitochondrial membrane. Under cellular stress, the pore opens, increasing the release of proapoptotic proteins, and ultimately resulting in cell death. MicroRNA-7 (miR-7) is a small non-coding RNA that has been found to exhibit a protective role in the cellular models of Parkinson disease. In the present study, miR-7 was predicted to regulate the function of mitochondria, according to gene ontology analysis of proteins that are down-regulated by miR-7. Indeed, miR-7 overexpression inhibited mitochondrial fragmentation, mitochondrial depolarization, cytochrome c release, reactive oxygen species generation, and release of mitochondrial calcium in response to 1-methyl-4-phenylpyridinium (MPP ؉ ) in human neuroblastoma SH-SY5Y cells. In addition, several of these findings were confirmed in mouse primary neurons. Among the mitochondrial proteins identified by gene ontology analysis, the expression of voltage-dependent anion channel 1 (VDAC1), a constituent of the mitochondrial permeability transition pore, was down-regulated by miR-7 through targeting 3-untranslated region of VDAC1 mRNA. Similar to miR-7 overexpression, knockdown of VDAC1 also led to a decrease in intracellular reactive oxygen species generation and subsequent cellular protection against MPP ؉ . Notably, overexpression of VDAC1 without the 3-UTR significantly abolished the protective effects of miR-7 against MPP ؉ -induced cytotoxicity and mitochondrial dysfunction, suggesting that the protective effect of miR-7 is partly exerted through promoting mitochondrial function by targeting VDAC1 expression. These findings point to a novel mechanism by which miR-7 accomplishes neuroprotection by improving mitochondrial health.The mitochondrial permeability transition pore (PTP), 2 which spans both the outer and the inner mitochondrial membranes, is a conductance channel responsible for maintaining the mitochondrial membrane potential. The mitochondrial PTP consists of three proteins: voltage-dependent anion channel 1 (VDAC1), adenine nucleotide transporter (ANT), and cyclophilin D (1). VDAC1 and ANT are integral membrane proteins of the outer and inner mitochondrial membranes, respectively. Together, these two proteins form the conductance channel of the mitochondrial PTP. Cyclophilin D is a mitochondrial matrix protein that associates with ANT and modulates pore function. Under normal physiological conditions, the mitochondrial PTP is maintained in a closed state, allowing mitochondria to remain polarized. Stressful stimuli, such as oxidative stress and accumulation of unfolded proteins, lead to the opening of the mitochondrial PTP (1). As a result, the mitochondrial membrane potential is dissipated, causing depolarization of mitochondria, decrease in ATP production, swelling of mitochondria, efflux of mitochondrial calcium, generation of reactive oxygen spec...

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“…Thus, the mechanism of MPP + toxicity is biphasic, namely (i) the DAT-mediated mechanism selective for dopaminergic neurons (at low concentrations) and (ii) the oxidative mechanism that occur a higher concentrations [160]. In SH-SY5Y and differentiated human neural progenitor ReNcell VM cells, microRNA-7 increases the neuronal expression of GLUT3 through targeted repression of RelA, which promotes glycolysis as evidenced by increased glucose consumption and lactate release, increased ATP and prevention against low dose MPP + -induced cell death [161]. …”

Section: Metabolic Disturbances In Sporadic Models Of Pdmentioning

confidence: 99%

Mitochondrial control of cell bioenergetics in Parkinson’s disease

Requejo-Aguilar

Bolaños

2016

Free Radical Biology and Medicine

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Parkinson disease (PD) is a neurodegenerative disorder characterized by a selective loss of dopaminergic neurons in the substantia nigra. The earliest biochemical signs of the disease involve failure in mitochondrial-endoplasmic reticulum cross talk and lysosomal function, mitochondrial electron chain impairment, mitochondrial dynamics alterations, and calcium and iron homeostasis abnormalities. These changes are associated with increased mitochondrial reactive oxygen species (mROS) and energy deficiency. Recently, it has been reported that, as an attempt to compensate for the mitochondrial dysfunction, neurons invoke glycolysis as a low-efficient mode of energy production in models of PD. Here, we review how mitochondria orchestrate the maintenance of cellular energetic status in PD, with special focus on the switch from oxidative phosphorylation to glycolysis, as well as the implication of endoplasmic reticulum and lysosomes in the control of bioenergetics.

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MicroRNA-7 Promotes Glycolysis to Protect against 1-Methyl-4-phenylpyridinium-induced Cell Death

Cited by 57 publications

References 36 publications

Glucose Metabolism and AMPK Signaling Regulate Dopaminergic Cell Death Induced by Gene (α-Synuclein)-Environment (Paraquat) Interactions

Glucose Metabolism and AMPK Signaling Regulate Dopaminergic Cell Death Induced by Gene (α-Synuclein)-Environment (Paraquat) Interactions

MicroRNA-7 Regulates the Function of Mitochondrial Permeability Transition Pore by Targeting VDAC1 Expression

Mitochondrial control of cell bioenergetics in Parkinson’s disease

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