Genetically Modeled Mice with Mutations in Mitochondrial Metabolic Enzymes for the Study of Cancer

Frontiers in Oncology

África eMillán-Uclés¹  Jose I Piruat¹ 

[1]Instituto de Biomedicina de Sevilla-Hospital Universitario Virgen del Rocio

关键词: Metabolism;    Mitochondria;    tumor;    mouse models;    Krebs'cycle;   

DOI  :  10.3389/fonc.2014.00200

来源: DOAJ

【 摘 要 】

Mitochondrial dysfunction has long been implicated in progression of cancer. As a paradigm, the Warburg effect, which by means of a switch towards anaerobic metabolism enables cancer cells to proliferate in oxygen limiting conditions, is well established. Besides this metabolic transformation of tumors, it has been discovered that mutations in genes encoding mitochondrial proteins are the etiological factor in different types of cancer. This confers to mitochondrial dysfunction a causative role, rather than resultant, in tumor genesis beyond its role in tumor progression and development. Mitochondrial proteins encoded by tumor suppressor genes are part of the succinate-dehydrogenase (SDH), the fumarate hydratase (FH), and the mitochondrial isocitrate-dehydrogenase (IDH) enzymes, all of them participating in the Krebs cycle. The spectrum of tumors associated with mutations in these genes is becoming larger and varies between each enzyme. Several mechanisms of tumorigenesis have been proposeds, most of them based on studies using cellular and animal models. Regarding the molecular pathways implicated in the oncogenic transformation, one of the first accepted theories was based on the constitutive expression of the hypoxia-inducible factor 1α (Hif1α) at normal oxygen tension, a theory referred to as pseudo-hypoxic drive. This mechanism has been linked to the three types of mutations, thus suggesting a central role in cancer. However, other alternatives molecular processes, such as oxidative stress or altered chromatin remodeling have been also proposed to play an onco-pathogenic role. In the recent years, the role of oncometabolites, a new concept emerged from biochemical studies, has acquired relevance as responsible for tumor formation. Nevertheless, the actual contribution of each of these mechanisms has not been definitively established. In this review, we summarize the results obtained from mouse strains genetically modified in the three different enzymes.

【 授权许可】

Unknown