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Published on: May 4, 2016
PGAM5 regulates PINK1/Parkin-mediated mitophagy via DRP1 in CCCP-induced mitochondrial dysfunction
Yun Sun Park1, Su Eun Choi1, Hyun Chul Koh2
1Department of Pharmacology, College of Medicine, Hanyang University, Seoul, Republic of Korea; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea.
Abstract:
Mitochondrial dynamics and mitophagy are critical processes for regulating mitochondrial homeostasis. Phosphoglycerate mutase family member 5 (PGAM5) is a mitochondrial protein that plays crucial roles in apoptosis and necroptosis, but the roles of PGAM5 in mitochondrial dynamics and mitophagy remain unclear. In this study, we investigated the role of PGAM5 in carbonyl cyanide m-chlorophenylhydrazone (CCCP)-induced mitochondrial damage and the correlation between mitochondrial dynamics and mitophagy using SH-SY5Y cells. We found that CCCP decreased mitochondrial membrane potential, resulting in mitochondrial dysfunction. CCCP increased PGAM5, dynamin-related protein 1 (DRP1), and optic atrophy 1 (OPA1) expression of the mitochondrial fraction in a time-dependent manner. Knockdown of PGAM5 inhibited DRP1 translocation without a change in OPA1 expression in CCCP-treated cells. Furthermore, knockdown of PGAM5 and DRP1 significantly blocked the increase of PTEN-induced putative protein kinase 1 (PINK1) and Parkin expression in the mitochondrial fraction of CCCP-treated cells. Interestingly, CCCP did not alter PINK1/Parkin expression in the mitochondrial fraction of OPA1 knockdown cells. Inhibiting mitophagy by PGAM5 knockdown accelerated CCCP-induced apoptosis. CCCP treatment also results in PINK1 stabilization on the mitochondrial membrane, which subsequently increases Parkin recruitment from the cytosol to abnormal mitochondria. In addition, we found that CCCP increased the level of mitochondrial LC3II, indicating that Parkin recruitment of PINK1 is a result of mitophagy. We propose that activation of PGAM5 is associated with DRP1 recruitment and PINK1 stabilization, which contribute to the modulation of mitophagy in CCCP-treated cells with mitochondrial dysfunction. In conclusion, we demonstrated that PGAM5 regulates PINK1-Parkin-mediated mitophagy, which can exert a neuroprotective effect against CCCP-induced apoptosis.
Insights
Phosphoglycerate mutase family member 5 (PGAM5) regulates mitophagy, a key process for mitochondrial health. PGAM5 activation is linked to neuroprotection against mitochondrial damage by promoting the PINK1-Parkin pathway.
Area of Science:
- Cell Biology
- Neuroscience
- Mitochondrial Biology
Background:
- Mitochondrial homeostasis is regulated by dynamics and mitophagy.
- Phosphoglycerate mutase family member 5 (PGAM5) is involved in apoptosis and necroptosis.
- The role of PGAM5 in mitochondrial dynamics and mitophagy is not well understood.
Purpose of the Study:
- To investigate PGAM5's role in CCCP-induced mitochondrial damage.
- To explore the correlation between mitochondrial dynamics and mitophagy.
- To elucidate PGAM5's function in the PINK1-Parkin mitophagy pathway.
Main Methods:
- Utilized SH-SY5Y cells treated with CCCP.
- Assessed mitochondrial membrane potential and mitochondrial dysfunction.
- Examined protein expression levels (PGAM5, DRP1, OPA1, PINK1, Parkin, LC3II) via western blotting.
- Performed knockdown experiments for PGAM5, DRP1, and OPA1.
Main Results:
- CCCP induced mitochondrial dysfunction and increased PGAM5, DRP1, and OPA1 levels.
- PGAM5 knockdown inhibited DRP1 translocation and PINK1/Parkin recruitment.
- OPA1 knockdown did not affect PINK1/Parkin levels.
- PGAM5 knockdown accelerated apoptosis, indicating a neuroprotective role.
Conclusions:
- PGAM5 activation is associated with DRP1 recruitment and PINK1 stabilization.
- PGAM5 modulates mitophagy in response to mitochondrial dysfunction.
- PGAM5 plays a crucial role in PINK1-Parkin-mediated mitophagy, offering neuroprotection against apoptosis.
