title: Mitochondrial fusion is regulated by Reaper to modulate Drosophila programmed cell death.
abstract: In most multicellular organisms, the decision to undergo programmed cell death in response to cellular damage or developmental cues is typically transmitted through mitochondria. It has been suggested that an exception is the apoptotic pathway of Drosophila melanogaster, in which the role of mitochondria remains unclear. Although IAP antagonists in Drosophila such as Reaper, Hid and Grim may induce cell death without mitochondrial membrane permeabilization, it is surprising that all three localize to mitochondria. Moreover, induction of Reaper and Hid appears to result in mitochondrial fragmentation during Drosophila cell death. Most importantly, disruption of mitochondrial fission can inhibit Reaper and Hid-induced cell death, suggesting that alterations in mitochondrial dynamics can modulate cell death in fly cells. We report here that Drosophila Reaper can induce mitochondrial fragmentation by binding to and inhibiting the pro-fusion protein MFN2 and its Drosophila counterpart dMFN/Marf. Our in vitro and in vivo analyses reveal that dMFN overexpression can inhibit cell death induced by Reaper or γ-irradiation. In addition, knockdown of dMFN causes a striking loss of adult wing tissue and significant apoptosis in the developing wing discs. Our findings are consistent with a growing body of work describing a role for mitochondrial fission and fusion machinery in the decision of cells to die.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: M
authors.initials: M
authors.lastname: Thomenius
authors.forename: C D
authors.initials: CD
authors.lastname: Freel
authors.forename: S
authors.initials: S
authors.lastname: Horn
authors.forename: R
authors.initials: R
authors.lastname: Krieser
authors.forename: E
authors.initials: E
authors.lastname: Abdelwahid
authors.forename: R
authors.initials: R
authors.lastname: Cannon
authors.forename: S
authors.initials: S
authors.lastname: Balasundaram
authors.forename: K
authors.initials: K
authors.lastname: White
authors.forename: S
authors.initials: S
authors.lastname: Kornbluth
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000528:radiation effects; D002460:Cell Line; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D005720:Gamma Rays; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding
chemical_list: D029721:Drosophila Proteins; C108880:HID protein, Drosophila; C527117:Marf protein, Drosophila; D008565:Membrane Proteins; D009479:Neuropeptides; C086973:rpr protein, Drosophila