Mitochondrial Structure, Function and Dynamics Are Temporally Controlled by c-Myc

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.

MYC inhibition induces metabolic changes leading to accumulation of lipid droplets in tumor cells

“…Likely, both aerobic glycolysis and efficient mitochondrial metabolism are important to support the energetic and biosynthetic demands of cancer cells (42). Several groups have established MYC's role in supporting mitochondrial biogenesis (9,10,35,43), and the most obvious metabolic consequence observed in our proteomic analysis was the down-regulation of multiple subunits comprising all complexes of the respiratory chain. Importantly, inhibitors of different complexes of the respiratory chain all induced a robust lipid accumulation.…”

“…Metabolic reprogramming is essential in cancer cells for adaptation to the tumor microenvironment and for maintenance of tumor growth (4,5). MYC is a potent regulator of these processes by inducing increased glycolysis and glutaminolysis (6,7) and by stimulating mitochondrial biogenesis and function (8)(9)(10). Several lines of experimental evidence support MYC as a therapeutic target (3,6,11,12).…”

Mitochondrial Citrate Transporter-dependent Metabolic Signature in the 22q11.2 Deletion Syndrome

“…In this case, the MYC-MAX (p ϭ 0.034; not shown) was significantly represented. The proto-oncogene MYC regulates glucose metabolism by inducing expression of key glycolytic enzymes, including lactate dehydrogenase and hexokinase, but also controls mitochondrial metabolism, because chronic depletion of MYC reduces mitochondrial mass, results in smaller and cristae-deficient mitochondria, and alters the dynamics of mitochondria fission and fusion, leading to reduced OXPHOS capacity (31,32). Like MYC, HIF-1␣ also promotes glycolysis by inducing expression of glycolytic enzymes, and, when MYC expression is deregulated in cancers (amplified or translocated), both MYC and HIF-1␣ cooperate to regulate glucose metabolism.…”

Mitochondrial dynamics and cancer

“…32,34 Importantly, these changes in mitochondrial dynamics were shown to be relevant for oncogene-mediated transformation and proliferation. Besides, p53, the most frequently mutated tumor suppressor gene, induced mitochondrial fragmentation and apoptosis when re-expressed in p53-mutated or null ovarian cancer cell lines.…”