mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

Abstract

Continuous proliferation of tumor cells requires constant adaptations of energy metabolism to rapidly fuel cell growth and division. This energetic adaptation often comprises deregulated glucose uptake and lactate production in the presence of oxygen, a process known as the "Warburg effect." For many years it was thought that the Warburg effect was a result of mitochondrial damage, however, unlike this proposal tumor cell mitochondria maintain their functionality, and is essential for integrating a variety of signals and adapting the metabolic activity of the tumor cell. The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of numerous cellular processes implicated in proliferation, metabolism, and cell growth. mTORC1 controls cellular metabolism mainly by regulating the translation and transcription of metabolic genes, such as peroxisome proliferator activated receptor γ coactivator-1 α (PGC-1α), sterol regulatory element-binding protein 1/2 (SREBP1/2), and hypoxia inducible factor-1 α (HIF-1α). Interestingly it has been shown that mTORC1 regulates mitochondrial metabolism, thus representing an important regulator in mitochondrial function. Here we present an overview on the role of mTORC1 in the regulation of mitochondrial functions in cancer, considering new evidences showing that mTORC1 regulates the translation of nucleus-encoded mitochondrial mRNAs that result in an increased ATP mitochondrial production. Moreover, we discuss the relationship between mTORC1 and glutaminolysis, as well as mitochondrial metabolites. In addition, mitochondrial fission processes regulated by mTORC1 and its impact on cancer are discussed. Finally, we also review the therapeutic efficacy of mTORC1 inhibitors in cancer treatments, considering its use in combination with other drugs, with particular focus on cellular metabolism inhibitors, that could help improve their anti neoplastic effect and eliminate cancer cells in patients.

Keywords: cancer; mTORC1; mitochondria; mitochondrial functions; therapy.

Figure 1

Mechanistic target of rapamycin complex 1 (mTORC1) and regulation of cellular processes. mTORC1 is a complex with DEPTOR and PRAS40 as negative regulators and RAPTOR and mSLT8 as positive regulators. Rapamycin-FKBP12 inhibits the mTOR kinase by directly blocking substrates recruitment and by further restricting active-site access. mTORC1 regulates different cellular processes such as ribosomal biogenesis, mRNA translation, autophagy, lipid and nucleotide synthesis, and mitochondrial functions.

Figure 2

Mechanistic target of rapamycin complex 1 (mTORC1) as a regulator of mitochondrial functions. mTORC1 can be activated by growth factor, and can regulate the mitochondrial biogenesis, mitophagy, fission and fusion processes, glutaminolysis, and mitochondrial oncometabolites generation.

Figure 3

Mechanistic target of rapamycin complex 1 (mTORC1) and mitochondrial biogenesis. mTORC1 promotes mitochondrial biogenesis via upregulation of translation genes and moreover via transcriptional regulation of TFAM, ATP50, NRF1, NRF2 genes.

Figure 4

Glutaminolysis and Mechanistic target of rapamycin complex 1 (mTORC1) The α-ketoglutarate (α-KG) produced by glutaminolysis is used for tricarboxilic acid (TCA) cycle intermediates replenish, a process known as anaplerosis. Once α-KG is exported from the mitochondria to the cytosol activates EGLNs, which in turn triggers mTORC1 activity promoting cell growth and inhibits autophagy.