Abstract
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.
Highlights
As one of the most frequently deregulated oncoproteins in human cancer [1,2] c-Myc exerts pleiotropic effects on proliferation, survival, cell cycle, size, differentiation, genomic stability, and metabolism [3,4,5,6]
Control of mitochondrial structure by Myc Initially, we employed three rat fibroblast lines: one with endogenous levels of Myc [33], an isogenic line bearing a homozygous deletion of myc [34], and myc2/2 cells stably transduced with a lentiviral vector encoding wild-type human Myc
Previous studies have shown that Myc regulates mitochondrial biogenesis and that many enzymes of the oxidative phosphorylation (OXPHOS) and glycolytic pathways are under direct Myc control [12,15,19]
Summary
As one of the most frequently deregulated oncoproteins in human cancer [1,2] c-Myc (hereafter, Myc) exerts pleiotropic effects on proliferation, survival, cell cycle, size, differentiation, genomic stability, and metabolism [3,4,5,6]. A significant number of Myc’s Pol II-regulated transcripts encode proteins involved in ribosome biosynthesis, aerobic and anaerobic metabolism, and mitochondrial biogenesis [12,13,14,15]. The metabolic reprogramming that results from Myc deregulation is exemplified by the ‘‘Warburg effect’’ whereby ATP originating from mitochondrial sources is largely supplanted by that derived from glycolysis, even in oxygen-rich environments [16]. Among the benefits thought to be afforded by the switch to this less efficient mode of energy generation is a redirecting of TCA intermediates away from ATP production and towards the synthesis of lipid, protein and nucleic acid precursors that serve the increased synthetic demands of the rapidly proliferating transformed cell [14,16,17,18]. The resultant increases in mitochondrial biogenesis and metabolism that accompany this reprogramming are at least partly explained by the ability of Myc to regulate the expression of TFAM, a major determinant of mitochondrial DNA replication [12], as well as PGC-1a [19] and PGC-1b [15], which regulate mitochondrial mass and energy metabolism [20]
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