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Abstract
BackgroundMitochondria are more than just the powerhouse of cells; they dictate if a cell dies or survives. Mitochondria are dynamic organelles that constantly undergo fusion and fission in response to environmental conditions. We showed previously that mitochondria of cells in a low oxygen environment (hypoxia) hyperfuse to form enlarged or highly interconnected networks with enhanced metabolic efficacy and resistance to apoptosis. Modifications to the appearance and metabolic capacity of mitochondria have been reported in cancer. However, the precise mechanisms regulating mitochondrial dynamics and metabolism in cancer are unknown. Since hypoxia plays a role in the generation of these abnormal mitochondria, we questioned if it modulates mitochondrial function. The mitochondrial outer-membrane voltage-dependent anion channel 1 (VDAC1) is at center stage in regulating metabolism and apoptosis. We demonstrated previously that VDAC1 was post-translationally C-terminal cleaved not only in various hypoxic cancer cells but also in tumor tissues of patients with lung adenocarcinomas. Cells with enlarged mitochondria and cleaved VDAC1 were also more resistant to chemotherapy-stimulated cell death than normoxic cancer cells.ResultsTranscriptome analysis of mouse embryonic fibroblasts (MEF) knocked out for Vdac1 highlighted alterations in not only cancer and inflammatory pathways but also in the activation of the hypoxia-inducible factor-1 (HIF-1) signaling pathway in normoxia. HIF-1α was stable in normoxia due to accumulation of reactive oxygen species (ROS), which decreased respiration and glycolysis and maintained basal apoptosis. However, in hypoxia, activation of extracellular signal-regulated kinase (ERK) in combination with maintenance of respiration and increased glycolysis counterbalanced the deleterious effects of enhanced ROS, thereby allowing Vdac1−/− MEF to proliferate better than wild-type MEF in hypoxia. Allografts of RAS-transformed Vdac1−/− MEF exhibited stabilization of both HIF-1α and HIF-2α, blood vessel destabilization, and a strong inflammatory response. Moreover, expression of Cdkn2a, a HIF-1-target and tumor suppressor gene, was markedly decreased. Consequently, RAS-transformed Vdac1−/− MEF tumors grew faster than wild-type MEF tumors.ConclusionsMetabolic reprogramming in cancer cells may be regulated by VDAC1 through vascular destabilization and inflammation. These findings provide new perspectives into the understanding of VDAC1 in the function of mitochondria not only in cancer but also in inflammatory diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s40170-015-0133-5) contains supplementary material, which is available to authorized users.
Highlights
Mitochondria are more than just the powerhouse of cells; they dictate if a cell dies or survives
High-throughput gene expression profiling of wild-type and Vdac1−/− mouse embryonic fibroblasts We confirmed that voltage-dependent anion channel (VDAC)-ΔC was produced in hypoxia in wild-type (Wt) MEF [14] and that the voltage-dependent anion channel 1 (VDAC1) protein was not expressed in Vdac1−/− MEF [5] (Fig. 1a)
To understand the functional relevance of differentially expressed up- and down-regulated genes in Vdac1−/− compared to Wt MEF, the microarray data were analyzed with Ingenuity Pathway AnalysisTM (IPATM) software using the same cut-offs for both cells lines
Summary
Mitochondria are more than just the powerhouse of cells; they dictate if a cell dies or survives. While the Warburg effect, or aerobic glycolysis, is considered to be primarily responsible for the metabolic reprogramming of cancer cells [1], mitochondrial respiration remains functional. It is not clear how mitochondria impact on proliferation or transformation of cancer cells, but as the «powerhouse» of cells, any change in metabolism can strongly influence the survival of the cancerous cell. VDAC1 is a pore that regulates the passage of molecules, including NADH, ATP/ADP, citrate, succinate, glutamate, pyruvate, and even glucose, as well as Mg2+, Ca2+, Cl−, K+, and Na+ ions [4] It regulates the mitochondrial phenotype, apoptosis, and glycolysis through binding to hexokinase I/II (HKI/II), the first enzyme of the glycolytic pathway. It is well known that the hypoxic nature of tumors is associated with poor clinical outcome, as hypoxia confers resistance to radio- and chemotherapy
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