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Inhibition of mitochondrial division through covalent modification of Drp1 protein by 15 deoxy-Delta(12,14)-prostaglandin J2.
- Source :
-
Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2010 Apr 23; Vol. 395 (1), pp. 17-24. Date of Electronic Publication: 2010 Mar 20. - Publication Year :
- 2010
-
Abstract
- Arachidonic acid derived endogenous electrophile 15d-PGJ2 has gained much attention in recent years due to its potent anti-proliferative and anti-inflammatory actions mediated through thiol modification of cysteine residues in its target proteins. Here, we show that 15d-PGJ2 at 1 microM concentration converts normal mitochondria into large elongated and interconnected mitochondria through direct binding to mitochondrial fission protein Drp1 and partial inhibition of its GTPase activity. Mitochondrial elongation induced by 15d-PGJ2 is accompanied by increased assembly of Drp1 into large oligomeric complexes through plausible intermolecular interactions. The role of decreased GTPase activity of Drp1 in the formation of large oligomeric complexes is evident when Drp1 is incubated with a non-cleavable GTP analog, GTPgammaS or by a mutation that inactivated GTPase activity of Drp1 (K38A). The mutation of cysteine residue (Cys644) in the GTPase effector domain, a reported target for modification by reactive electrophiles, to alanine mimicked K38A mutation induced Drp1 oligomerization and mitochondrial elongation, suggesting the importance of cysteine in GED to regulate the GTPase activity and mitochondrial morphology. Interestingly, treatment of K38A and C644A mutants with 15d-PGJ2 resulted in super oligomerization of both mutant Drp1s indicating that 15d-PGJ2 may further stabilize Drp1 oligomers formed by loss of GTPase activity through covalent modification of middle domain cysteine residues. The present study documents for the first time the regulation of a mitochondrial fission activity by a prostaglandin, which will provide clues for understanding the pathological and physiological consequences of accumulation of reactive electrophiles during oxidative stress, inflammation and degeneration.<br /> (2010 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Cell Line
Cysteine genetics
Dynamins genetics
Dynamins metabolism
GTP Phosphohydrolases antagonists & inhibitors
GTP Phosphohydrolases genetics
HeLa Cells
Humans
Microtubule-Associated Proteins genetics
Mitochondria physiology
Mitochondrial Proteins genetics
Mutation
Prostaglandin D2 pharmacology
Protein Structure, Tertiary genetics
Rats
GTP Phosphohydrolases metabolism
Microtubule-Associated Proteins metabolism
Mitochondria drug effects
Mitochondrial Proteins metabolism
Prostaglandin D2 analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2104
- Volume :
- 395
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Biochemical and biophysical research communications
- Publication Type :
- Academic Journal
- Accession number :
- 20307494
- Full Text :
- https://doi.org/10.1016/j.bbrc.2010.03.093