myc(-/-) rat fibroblasts (KO cells) differ from myc(+/+) (WT) cells and KO cells with enforced Myc re-expression (KO-Myc cells) with respect to mitochondrial structure and function, utilization of
glucose and
glutamine as energy-generating substrates, and
ATP levels. Specifically, KO cells demonstrate low levels of glycolysis and oxidative phosphorylation, dysfunctional mitochondria and electron transport chain complexes, and depleted
ATP stores. We examined here how these cells adapt to their energy-deficient state and how they differ in their uptake and utilization of long- and medium-chain
fatty acids such as
palmitate and
octanoate, respectively. Metabolic tracing of these molecules showed that KO cells preferentially utilize them as β-oxidation substrates and that, rather than directing them into
phospholipids, preferentially store them as neutral
lipids. KO cell transcriptional profiling and functional assays revealed a generalized up-regulation of pathways involved in
fatty acid transport and catabolism as well as evidence that these cells attempt to direct
acetyl-CoA into the
tricarboxylic acid (TCA) cycle for
ATP production rather than utilizing it for anabolic purposes. Additional evidence to support this idea included the finding that
AMP-dependent
protein kinase was constitutively activated in KO cells. The complex control of
pyruvate dehydrogenase, which links glycolysis to the TCA cycle, was also maximized to ensure the conversion of
pyruvate to
acetyl-CoA. Despite these efforts to maximize
acetyl-CoA for energy-generating purposes, its levels remained chronically low in KO cells. This suggests that
tumor cells with Myc deregulation might be susceptible to novel
therapies that limit
acetyl-CoA availability.