Drp1 stabilizes p53 on the mitochondria to trigger necrosis under oxidative stress conditions in vitro and in vivo.
Oxidative-stress-induced necrosis is considered to be one of the main pathological mediators in various neurological disorders, such as brain ischaemia. However, little is known about the mechanism by which cells modulate necrosis in response to oxidative stress. In the present study, we showed that Drp1 (dynamin-related protein 1), a primary mitochondrial fission protein, stabilizes the well-known stress gene p53 and is required for p53 translocation to the mitochondria under conditions of oxidative stress. We found that Drp1 binding to p53 induced mitochondria-related necrosis. In contrast, inhibition of Drp1 hyperactivation by Drp1 siRNA reduced necrotic cell death in cell cultures exposed to oxidative stress. Most significantly, we demonstrated that inhibition of Drp1 by the Drp1 peptide inhibitor P110, which was developed recently by our group, abolished p53 association with the mitochondria and reduced brain infarction in rats subjected to brain ischaemia/reperfusion injury. Taken together, these findings reveal a novel mechanism of Drp1 hyperactivation in the induction of mitochondrial damage and subsequent cell death. We propose that a Drp1 inhibitor such as P110 is a possible therapeutic agent for diseases in which hyperactivated Drp1 contributes to the pathology.
*Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, U.S.A.
Xing
X
Guo
†Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, U.S.A.
Hiromi
H
Sesaki
Xin
X
Qi
D000818:Animals; D020520:Brain Infarction / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D016923:Cell Death / Q000235:genetics; D002478:Cells, Cultured; D034281:Dynamins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis; D018384:Oxidative Stress / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; C486391:Dnm1l protein, mouse; D034281:Dynamins