Mitochondrial structure, function and dynamics are temporally controlled by c-Myc.
Although the c-Myc (Myc) oncoprotein controls mitochondrial biogenesis and multiple enzymes involved in oxidative phosphorylation (OXPHOS), the coordination of these events and the mechanistic underpinnings of their regulation remain largely unexplored. We show here that re-expression of Myc in myc-/- fibroblasts is accompanied by a gradual accumulation of mitochondrial biomass and by increases in membrane polarization and mitochondrial fusion. A correction of OXPHOS deficiency is also seen, although structural abnormalities in electron transport chain complexes (ETC) are not entirely normalized. Conversely, the down-regulation of Myc leads to a gradual decrease in mitochondrial mass and a more rapid loss of fusion and membrane potential. Increases in the levels of proteins specifically involved in mitochondrial fission and fusion support the idea that Myc affects mitochondrial mass by influencing both of these processes, albeit favoring the latter. The ETC defects that persist following Myc restoration may represent metabolic adaptations, as mitochondrial function is re-directed away from producing ATP to providing a source of metabolic precursors demanded by the transformed cell.
Division of Hematology/Oncology, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, United States of America. gravja@chp.edu
J Anthony
JA
Graves
Yudong
Y
Wang
Sunder
S
Sims-Lucas
Edward
E
Cherok
Kristi
K
Rothermund
Maria F
MF
Branca
Jennifer
J
Elster
Donna
D
Beer-Stolz
Bennett
B
Van Houten
Jerry
J
Vockley
Edward V
EV
Prochownik
D000818:Animals; D002460:Cell Line; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D051381:Rats
D004272:DNA, Mitochondrial; D016271:Proto-Oncogene Proteins c-myc