title: Exogenous cardiolipin localizes to mitochondria and prevents TAZ knockdown-induced apoptosis in myeloid progenitor cells.
abstract: The concentration and composition of cardiolipin (CL) in mitochondria are altered in age-related heart disease, Barth Syndrome, and other rare genetic disorders, resulting in mitochondrial dysfunction. To explore whether exogenous CL can be delivered to cells, CL was combined with apolipoprotein A-I to generate water-soluble, nanoscale complexes termed nanodisks (ND). Mass spectrometry of HL60 myeloid progenitor cell extracts revealed a 30-fold increase in cellular CL content following incubation with CL-ND. When CL-ND containing a fluorescent CL analogue was employed, confocal microscopy revealed CL localization to mitochondria. The ability of CL-ND to elicit a physiological response was examined in an HL60 cell culture model of Barth Syndrome neutropenia. siRNA knockdown of the phospholipid transacylase, tafazzin (TAZ), induced apoptosis in these cells. When TAZ knockdown cells were incubated with CL-ND, the apoptotic response was attenuated. Thus, CL-ND represent a potential intervention strategy for replenishment of CL in Barth Syndrome, age-related heart disease, and other disorders characterized by depletion of this key mitochondrial phospholipid.
authors.affiliation: Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland CA, 94609, United States.
authors.forename: Nikita
authors.initials: N
authors.lastname: Ikon
authors.affiliation: Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland CA, 94609, United States.
authors.forename: Betty
authors.initials: B
authors.lastname: Su
authors.affiliation: Department of Medicine, Campus Box 8127, Washington University School of Medicine, 660S. Euclid Ave, St. Louis, MO 63110, United States.
authors.forename: Fong-Fu
authors.initials: FF
authors.lastname: Hsu
authors.affiliation: Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland CA, 94609, United States.
authors.forename: Trudy M
authors.initials: TM
authors.lastname: Forte
authors.affiliation: Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland CA, 94609, United States. Electronic address: rryan@chori.org.
authors.forename: Robert O
authors.initials: RO
authors.lastname: Ryan
mesh_terms: D000217:Acyltransferases; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002308:Cardiolipins / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D023461:Myeloid Progenitor Cells / Q000473:pathology*; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D017304:Annexin A5; D002308:Cardiolipins; D014157:Transcription Factors; D000217:Acyltransferases; C108675:TAFAZZIN protein, human
keywords: Barth syndrome; Cardiolipin nanodisk; HL60 myeloid progenitor cells; Heart disease; Mitochondrial dysfunction; Neutropenia