Solid tumors, including the aggressive primary brain cancer glioblastoma multiforme, develop resistance to cell death, in part as a result of a switch from mitochondrial oxidative phosphorylation to cytoplasmic glycolysis. This metabolic remodeling is accompanied by mitochondrial hyperpolarization. We tested whether the small-molecule and orphan drug dichloroacetate (DCA) can reverse this cancer-specific metabolic and mitochondrial remodeling in glioblastoma. Freshly isolated glioblastomas from 49 patients showed mitochondrial hyperpolarization, which was rapidly reversed by DCA. In a separate experiment with five patients who had glioblastoma, we prospectively secured baseline and serial tumor tissue, developed patient-specific cell lines of glioblastoma and putative glioblastoma stem cells (CD133(+), nestin(+) cells), and treated each patient with oral DCA for up to 15 months. DCA depolarized mitochondria, increased mitochondrial reactive oxygen species, and induced apoptosis in GBM cells, as well as in putative GBM stem cells, both in vitro and in vivo. DCA therapy also inhibited the hypoxia-inducible factor-1alpha, promoted p53 activation, and suppressed angiogenesis both in vivo and in vitro. The dose-limiting toxicity was a dose-dependent, reversible peripheral neuropathy, and there was no hematologic, hepatic, renal, or cardiac toxicity. Indications of clinical efficacy were present at a dose that did not cause peripheral neuropathy and at serum concentrations of DCA sufficient to inhibit the target enzyme of DCA, pyruvate dehydrogenase kinase II, which was highly expressed in all glioblastomas. Metabolic modulation may be a viable therapeutic approach in the treatment of glioblastoma.

DNA transcription, replication, and repair are regulated by histone acetylation, a process that requires the generation of acetyl-coenzyme A (CoA). Here, we show that all the subunits of the mitochondrial pyruvate dehydrogenase complex (PDC) are also present and functional in the nucleus of mammalian cells. We found that knockdown of nuclear PDC in isolated functional nuclei decreased the de novo synthesis of acetyl-CoA and acetylation of core histones. Nuclear PDC levels increased in a cell-cycle-dependent manner and in response to serum, epidermal growth factor, or mitochondrial stress; this was accompanied by a corresponding decrease in mitochondrial PDC levels, suggesting a translocation from the mitochondria to the nucleus. Inhibition of nuclear PDC decreased acetylation of specific lysine residues on histones important for G1-S phase progression and expression of S phase markers. Dynamic translocation of mitochondrial PDC to the nucleus provides a pathway for nuclear acetyl-CoA synthesis required for histone acetylation and epigenetic regulation.

In pulmonary arterial hypertension (PAH), antiapoptotic, proliferative, and inflammatory diatheses converge to create an obstructive vasculopathy. A selective down-regulation of the Kv channel Kv1.5 has been described in human and animal PAH. The resultant increase in intracellular free Ca 2؉ ([Ca 2؉ ]i) and K ؉ ([K ؉ ]i) concentrations explains the pulmonary artery smooth muscle cell (PASMC) contraction, proliferation and resistance to apoptosis. The recently described PASMC hyperpolarized mitochondria and increased bcl-2 levels also contribute to apoptosis resistance in PAH. The cause of the Kv1.5, mitochondrial, and inflammatory abnormalities remains unknown. We hypothesized that these abnormalities can be explained in part by an activation of NFAT (nuclear factor of activated T cells), a Ca 2؉ / calcineurin-sensitive transcription factor. We studied PASMC and lungs from six patients with and four without PAH and blood from 23 PAH patients and 10 healthy volunteers.

Pulmonary arterial hypertension is caused by excessive growth of vascular cells that eventually obliterate the pulmonary arterial lumen, causing right ventricular failure and premature death. Despite some available treatments, its prognosis remains poor, and the cause of the vascular remodeling remains unknown. The vascular smooth muscle cells that proliferate during pulmonary arterial hypertension are characterized by mitochondrial hyperpolarization, activation of the transcription factor NFAT (nuclear factor of activated T cells), and down-regulation of the voltage-gated potassium channel Kv1.5, all of which suppress apoptosis. We found that mice lacking the gene for the metabolic enzyme malonyl-coenzyme A (CoA) decarboxylase (MCD) do not show pulmonary vasoconstriction during exposure to acute hypoxia and do not develop pulmonary arterial hypertension during chronic hypoxia but have an otherwise normal phenotype. The lack of MCD results in an inhibition of fatty acid oxidation, which in turn promotes glucose oxidation and prevents the shift in metabolism toward glycolysis in the vascular media, which drives the development of pulmonary arterial hypertension in wild-type mice. Clinically used metabolic modulators that mimic the lack of MCD and its metabolic effects normalize the mitochondrial-NFAT-Kv1.5 defects and the resistance to apoptosis in the proliferated smooth muscle cells, reversing the pulmonary hypertension induced by hypoxia or monocrotaline in mice and rats, respectively. This study of fatty acid oxidation and MCD identifies a critical role for metabolism in both the normal pulmonary circulation (hypoxic pulmonary vasoconstriction) and pulmonary hypertension, pointing to several potential therapeutic targets for the treatment of this deadly disease.

Pulmonary arterial hypertension (PAH) is a vascular remodeling disease of the lungs resulting in heart failure and premature death. Although, until recently, it was thought that PAH pathology is restricted to pulmonary arteries, several extrapulmonary organs are also affected. The realization that these tissues share a common metabolic abnormality (i.e., suppression of mitochondrial glucose oxidation and increased glycolysis) is important for our understanding of PAH, if not a paradigm shift. Here, we discuss an emerging metabolic theory, which proposes that PAH should be viewed as a syndrome involving many organs sharing a mitochondrial abnormality and explains many PAH features and provides novel biomarkers and therapeutic targets.