Impaired mitochondrial biogenesis contributes to depletion of functional mitochondria in chronic MPP+ toxicity: dual roles for ERK1/2

Zhu, Jianhui; Gusdon, Aaron M.; Çimen, Hüseyin; Houten, B A Van; Koc, Emine C.; Chu, Charleen T.

doi:10.1038/cddis.2012.46

Cited by 92 publications

(89 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…8A). We previously reported that MPP+ treatment induces mitophagy accompanied by decreased expression of mitochondrial respiratory complex proteins (Zhu et al, 2012; Zhu et al, 2007). Overexpression of wild-type TFAM can completely rescue the loss of respiratory complex proteins, in the chronic MPP+ model, restoring mitochondrial protein synthesis.…”

Section: Resultsmentioning

confidence: 99%

“…Protein concentration was determined by Coomassie Blue Protein Assay (Pierce, Rockford, IL). Western blot analysis was performed as described previously (Zhu et al, 2012). The post-translational modification of TFAM was analyzed by 2D immunoblotting procedures using an isoelectric focusing (IEF) apparatus and IPG strips pH 3–10 (Protean IEF Cell, Bio-Rad) followed by SDS-PAGE and immunoblotting, according to the manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

“…However, the molecular mechanisms by which TFAM function is regulated under physiological or pathological conditions have yet to be fully elucidated. Chronic challenge of neuronal cells with lower doses of the complex I inhibitor 1-methyl-4-phenylpyridinium (MPP+) results in suppression of mitochondrial biogenesis and induction of mitophagy (Zhu et al, 2012). Inhibiting ERK activation restores mitochondrial content and function to a much greater extent than manipulating mitophagy, suggesting an important effect on mitochondrial biogenesis.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

ERK-mediated phosphorylation of TFAM downregulates mitochondrial transcription: Implications for Parkinson's disease

et al. 2014

View full text Add to dashboard Cite

Mitochondrial transcription factor A (TFAM) regulates mitochondrial biogenesis, which is downregulated by extracellular signal-regulated protein kinases (ERK1/2) in cells treated chronically with the complex I inhibitor 1-methyl-4-phenylpyridinium (MPP+). We utilized mass spectrometry to identify ERK1/2-dependent TFAM phosphorylation sites. Mutation of TFAM at serine 177 to mimic phosphorylation recapitulated the effects of MPP+ in decreasing the binding of TFAM to the light strand promoter, suppressing mitochondrial transcription. Mutant TFAM was unable to affect respiratory function or rescue the effects of MPP+ on respiratory complexes. These data disclose a novel mechanism by which ERK1/2 regulates mitochondrial function through direct phosphorylation of TFAM.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

ERK-mediated phosphorylation of TFAM downregulates mitochondrial transcription: Implications for Parkinson's disease

et al. 2014

View full text Add to dashboard Cite

show abstract

“…4,20 Similarly to Table 1). [40][41][42] Rotenone in particular causes a relatively mild mitochondrial depolarization, which is inadequate to induce PINK1-mediated mitophagy in primary neurons or neuroblastoma cells. 41 Rotenone, as well as 6-OHDA (and so does Staurosporine) activate the process by promoting the externalization of cardiolipin, which recruits the autophagic machinery via a direct interaction with LC3 ( Figure 2c).…”

Section: Parkinsonian Toxinsmentioning

confidence: 99%

The pharmacological regulation of cellular mitophagy

2017

View full text Add to dashboard Cite

Small molecules are pharmacological tools of considerable value in dissecting complex biological processes and identifying potential therapeutic interventions.Recently, the cellular quality control process of mitophagy attracted considerable research interest, however, the limited availability of suitable chemical probes restricted our understanding of the molecular mechanisms involved.Current approaches to initiate mitophagy include acute dissipation of the mitochondrial membrane potential (ΔΨm) by mitochondrial uncouplers (e.g. FCCP/CCCP), or the use of Antimycin A/Oligomycin to impair respiration. Both approaches impair mitochondrial homeostasis, and therefore limit the scope for dissection of subtle, bio-energy related regulatory phenomena.Recently, novel mitophagy activators acting independently of the respiration collapse have been reported, offering new opportunities to understand the process and potential for therapeutic exploitation.We have therefore summarized the current status of mitophagy modulators and analyzed the available chemical tools, commenting on their advantages, limitations and current applications.

show abstract

“…JC-1 Labeling-JC-1 labeling was performed as described previously (21). In brief, cells were loaded with JC-1 dye (5 g/ml) for 30 min at 37°C in the dark.…”

Section: Materials-mppmentioning

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

106

View full text Add to dashboard Cite

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...

show abstract

Impaired mitochondrial biogenesis contributes to depletion of functional mitochondria in chronic MPP+ toxicity: dual roles for ERK1/2

Cited by 92 publications

References 40 publications

ERK-mediated phosphorylation of TFAM downregulates mitochondrial transcription: Implications for Parkinson's disease

ERK-mediated phosphorylation of TFAM downregulates mitochondrial transcription: Implications for Parkinson's disease

The pharmacological regulation of cellular mitophagy

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

Contact Info

Product

Resources

About