title: Alterations in c-Myc phenotypes resulting from dynamin-related protein 1 (Drp1)-mediated mitochondrial fission.
abstract: The c-Myc (Myc) oncoprotein regulates numerous phenotypes pertaining to cell mass, survival and metabolism. Glycolysis, oxidative phosphorylation (OXPHOS) and mitochondrial biogenesis are positively controlled by Myc, with myc-/- rat fibroblasts displaying atrophic mitochondria, structural and functional defects in electron transport chain (ETC) components, compromised OXPHOS and ATP depletion. However, while Myc influences mitochondrial structure and function, it is not clear to what extent the reverse is true. To test this, we induced a state of mitochondrial hyper-fission in rat fibroblasts by de-regulating Drp1, a dynamin-like GTPase that participates in the terminal fission process. The mitochondria from these cells showed reduced mass and interconnectivity, a paucity of cristae, a marked reduction in OXPHOS and structural and functional defects in ETC Complexes I and V. High rates of abortive mitochondrial fusion were observed, likely reflecting ongoing, but ultimately futile, attempts to normalize mitochondrial mass. Cellular consequences included reduction of cell volume, ATP depletion and activation of AMP-dependent protein kinase. In response to Myc deregulation, apoptosis was significantly impaired both in the absence and presence of serum, although this could be reversed by increasing ATP levels by pharmacologic means. The current work demonstrates that enforced mitochondrial fission closely recapitulates a state of Myc deficiency and that mitochondrial integrity and function can affect Myc-regulated cellular behaviors. The low intracellular ATP levels that are frequently seen in some tumors as a result of inadequate vascular perfusion could favor tumor survival by countering the pro-apoptotic tendencies of Myc overexpression.
authors.affiliation: Division of Hematology/Oncology, Children's Hospital of Pittburgh of UPMC, Pittsburgh, PA 15224, USA.
authors.forename: M
authors.initials: M
authors.lastname: Sarin
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: F
authors.initials: F
authors.lastname: Zhang
authors.forename: K
authors.initials: K
authors.lastname: Rothermund
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: J
authors.initials: J
authors.lastname: Lu
authors.forename: S
authors.initials: S
authors.lastname: Sims-Lucas
authors.forename: D
authors.initials: D
authors.lastname: Beer-Stolz
authors.forename: B E
authors.initials: BE
authors.lastname: Van Houten
authors.forename: J
authors.initials: J
authors.lastname: Vockley
authors.forename: E S
authors.initials: ES
authors.lastname: Goetzman
authors.forename: J Anthony
authors.initials: JA
authors.lastname: Graves
authors.forename: E V
authors.initials: EV
authors.lastname: Prochownik
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D034281:Dynamins / Q000502:physiology*; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D006801:Humans; D063154:Mitochondrial Dynamics; D010085:Oxidative Phosphorylation; D010641:Phenotype; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D012265:Ribonucleotides / Q000502:physiology
chemical_list: D045222:Electron Transport Chain Complex Proteins; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D000255:Adenosine Triphosphate; C519851:Dnm1l protein, rat; D034281:Dynamins; C031143:AICA ribonucleotide