CCCP induces autophagy in an AMPK-independent manner
Abstract
AMP-activated protein kinase (AMPK) is an important sensor of cellular energy status, and is involved in cell growth and autophagy through mammalian target of rapamycin complex 1 (mTORC1). Carbonyl cyanide m-chlorophenylhydrazone (CCCP), a mitochondrial uncoupler, leads to AMPK activation and Parkin-dependent mitophagy, respectively. However, the detailed biochemical mechanism of how CCCP induces autophagy or mitophagy has not been investigated yet. Here, we showed that CCCP inhibits mTORC1 independently of AMPK, although CCCP induces AMPK activation. Using wild type (WT) and AMPKα1/α2 double knockout (DKO) MEFs, we observed that CCCP promotes endogenous LC3 lipidation and formation of RFP-LC3 puncta, indicating autophagosome or autolysosome, in an AMPK-independent manner. Finally, we also revealed that the percentage of CCCP-dependent colocalization between mitochondria and RFP-LC3 puncta is similar both in WT and AMPKα1/α2 DKO MEFs. Based on these data, we concluded that AMPK is not essential in regulation of CCCP-induced autopahgy including mitophagy.
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The positive effect of mitochondrial uncoupling on autophagy has been established in many cellular and animal models, including adipocytes, MEFs, HeLa cells, HepG2 cells, SH-SY5Y neuroblastoma cells, and C57BL6 mice.
“The positive effect of mitochondrial uncoupling on autophagy has been established in many cellular and animal models, including adipocytes [91], MEFs [92], HeLa cells [93], HepG2 cells [90], SH-SY5Y neuroblastoma cells [93], or C57BL6 mice [94].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [92]
CCCP inhibits mTORC1 independently of AMPK.
“The role of AMPK activation, in response to a decrease in the ATP/AMP ratio caused by mitochondrial uncoupling as a requirement for mitophagy activation, has been questioned as CCCP is able to inhibit the activity of mTORC1 independently of AMPK [92].”
From Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases (2019) · cites this paper as [92]
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- Authors
- Kwon, K.-Y., Viollet, B., & Yoo, O. J.
- Affiliations
- Korea Advanced Institute of Science and Technology (KR)
- Corresponding author
- Yoo, Ook Joon
- ORCID
- Kwon, Kyum-Yil
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 2011-12
- Volume
- 416
- Issue
- 3-4
- Pages
- 343-348
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W2045081864
- Cited by
- 55
- References
- 22
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 2 · 2022: 2 · 2021: 5 · 2020: 7 · 2019: 4 · 2018: 2 · 2017: 4 · 2016: 5 · 2015: 11 · 2014: 1 · 2013: 6 · 2012: 1
- FWCI
- 1.93
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- CCCP, autophagy, AMPK, mTORC1, mitophagy, mitochondrial uncouplers, LC3 lipidation
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, AMP-Activated Protein Kinase Kinases, Animals, Autophagy, Carbonyl Cyanide m-Chlorophenyl Hydrazone, Humans, Protein Kinases, Proteins, Mice, Knockout, Multiprotein Complexes, Mice, HEK293 Cells, TOR Serine-Threonine Kinases
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