Abstract
BackgroundAerobic glycolysis, namely the Warburg effect, is the main hallmark of cancer cells. Mitochondrial respiratory dysfunction has been proposed to be one of the major causes for such glycolytic shift. This hypothesis has been revisited as tumors appear to undergo waves of gene regulation during progression, some of which rely on functional mitochondria. In this framework, the role of mitochondrial complex I is still debated, in particular with respect to the effect of mitochondrial DNA mutations in cancer metabolism. The aim of this work is to provide the proof of concept that functional complex I is necessary to sustain tumor progression.MethodsComplex I-null osteosarcoma cells were complemented with allotopically expressed complex I subunit 1 (MT-ND1). Complex I re-assembly and function recovery, also in terms of NADH consumption, were assessed. Clones were tested for their ability to grow in soft agar and to generate tumor masses in nude mice. Hypoxia levels were evaluated via pimonidazole staining and hypoxia-inducible factor-1α (HIF-1α) immunoblotting and histochemical staining. 454-pyrosequencing was implemented to obtain global transcriptomic profiling of allotopic and non-allotopic xenografts.ResultsComplementation of a truncative mutation in the gene encoding MT-ND1, showed that a functional enzyme was required to perform the glycolytic shift during the hypoxia response and to induce a Warburg profile in vitro and in vivo, fostering cancer progression. Such trigger was mediated by HIF-1α, whose stabilization was regulated after recovery of the balance between α-ketoglutarate and succinate due to a recuperation of NADH consumption that followed complex I rescue.ConclusionRespiratory complex I is essential for the induction of Warburg effect and adaptation to hypoxia of cancer cells, allowing them to sustain tumor growth. Differently from other mitochondrial tumor suppressor genes, therefore, a complex I severe mutation such as the one here reported may confer anti-tumorigenic properties, highlighting the prognostic values of such genetic markers in cancer.
Highlights
Aerobic glycolysis, namely the Warburg effect, is the main hallmark of cancer cells
We have recently shown that a dysfunction in complex I (CI), caused by the severe m.3571insC/MT-NADH dehydrogenase subunit 1 (ND1) mitochondrial DNA mutation, strongly contributes to hypoxia inducible factor-1α (HIF-1α) destabilization and lack of hypoxia adaptation, which eventually leads to an antitumorigenic effect [14,15]
In the attempt to assign a role to CI within the Warburg effect, we have demonstrated that this mitochondrial enzyme is required in order to perform the metabolic switch towards glycolysis during the hypoxia response, a pivotal goal in the metabolic reprogramming of cancer cells
Summary
Mitochondrial respiratory dysfunction has been proposed to be one of the major causes for such glycolytic shift This hypothesis has been revisited as tumors appear to undergo waves of gene regulation during progression, some of which rely on functional mitochondria. The seminal observation by Otto Warburg at the beginning of last century [1,2] has fostered compelling efforts in elucidating the profound metabolic changes that transformed cells undergo from initial tumor to the spread of metastases, which to date remain largely obscure It is still unclear why highly proliferative and invasive cancer cells settle for an energetically less efficient aerobic glycolysis, rather than oxidative phosphorylation (OXPHOS), which generates far more ATP from a single glucose molecule. Mitochondria are involved in the regulation of hypoxic adaptation [9], a process that must be triggered in any solid neoplasia to overcome the initial steps of tumorigenesis and is controlled by hypoxia-inducible factor 1α (HIF-1α) [10]
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