title: Lysocardiolipin acyltransferase 1 (ALCAT1) controls mitochondrial DNA fidelity and biogenesis through modulation of MFN2 expression.
abstract: Oxidative stress causes mitochondrial fragmentation and dysfunction in age-related diseases through unknown mechanisms. Cardiolipin (CL) is a phospholipid required for mitochondrial oxidative phosphorylation. The function of CL is determined by its acyl composition, which is significantly altered by the onset of age-related diseases. Here, we examine a role of acyl-CoA:lysocardiolipin acyltransferase lysocardiolipin acyltransferase 1 (ALCAT1), a lysocardiolipin acyltransferase that catalyzes pathological CL remodeling, in mitochondrial biogenesis. We show that overexpression of ALCAT1 causes mitochondrial fragmentation through oxidative stress and depletion of mitofusin mitofusin 2 (MFN2) expression. Strikingly, ALCAT1 overexpression also leads to mtDNA instability and depletion that are reminiscent of MFN2 deficiency. Accordingly, expression of MFN2 completely rescues mitochondrial fusion defect and respiratory dysfunction. Furthermore, ablation of ALCAT1 prevents mitochondrial fragmentation from oxidative stress by up-regulating MFN2 expression, mtDNA copy number, and mtDNA fidelity. Together, these findings reveal an unexpected role of CL remodeling in mitochondrial biogenesis, linking oxidative stress by ALCAT1 to mitochondrial fusion defect.
authors.affiliation: Shaanxi Center for Stem Cell Engineering and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Liu
authors.forename: Huayan
authors.initials: H
authors.lastname: Wang
authors.forename: Weiping
authors.initials: W
authors.lastname: Zhang
authors.forename: David C
authors.initials: DC
authors.lastname: Chan
authors.forename: Yuguang
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000217:Acyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002308:Cardiolipins / Q000378:metabolism; D002460:Cell Line; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D042822:Genomic Instability; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D008954:Models, Biological; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D002308:Cardiolipins; D004272:DNA, Mitochondrial; D012333:RNA, Messenger; D000217:Acyltransferases; C525544:lysocardiolipin acyltransferase, mouse; D020558:GTP Phosphohydrolases; C488750:Mfn1 protein, mouse; C488751:Mfn2 protein, mouse; C498809:Opa1 protein, mouse