Mitochondrial remodeling following fission inhibition by 15d-PGJ2 involves molecular changes in mitochondrial fusion protein OPA1.
We showed earlier that 15 deoxy Delta(12,14) prostaglandin J2 (15d-PGJ2) inactivates Drp1 and induces mitochondrial fusion [1]. However, prolonged incubation of cells with 15d-PGJ2 resulted in remodeling of fused mitochondria into large swollen mitochondria with irregular cristae structure. While initial fusion of mitochondria by 15d-PGJ2 required the presence of both outer (Mfn1 and Mfn2) and inner (OPA1) mitochondrial membrane fusion proteins, later mitochondrial changes involved increased degradation of the fusion protein OPA1 and ubiquitination of newly synthesized OPA1 along with decreased expression of Mfn1 and Mfn2, which likely contributed to the loss of tubular rigidity, disorganization of cristae, and formation of large swollen degenerated dysfunctional mitochondria. Similar to inhibition of Drp1 by 15d-PGJ2, decreased expression of fission protein Drp1 by siRNA also resulted in the loss of fusion proteins. Prevention of 15d-PGJ2 induced mitochondrial elongation by thiol antioxidants prevented not only loss of OPA1 isoforms but also its ubiquitination. These findings provide novel insights into unforeseen complexity of molecular events that modulate mitochondrial plasticity.
Kar
Rekha
R
Department of Pathology, UT Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Mishra
Nandita
N
Singha
Prajjal K
PK
Venkatachalam
Manjeri A
MA
Saikumar
Pothana
P
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D064550:Death-Associated Protein Kinases; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D008933:Mitochondrial Swelling / Q000187:drug effects*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D054875:Ubiquitination
C477819:15-deoxyprostaglandin J2; D051017:Apoptosis Regulatory Proteins; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020558:GTP Phosphohydrolases; C488750:Mfn1 protein, mouse; C488751:Mfn2 protein, mouse; C498809:Opa1 protein, mouse; D015230:Prostaglandin D2