Mitochondria and Cancer - PubMed (original) (raw)

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Mitochondria and Cancer

Sejal Vyas et al. Cell. 2016.

Abstract

Mitochondria are bioenergetic, biosynthetic, and signaling organelles that are integral in stress sensing to allow for cellular adaptation to the environment. Therefore, it is not surprising that mitochondria are important mediators of tumorigenesis, as this process requires flexibility to adapt to cellular and environmental alterations in addition to cancer treatments. Multiple aspects of mitochondrial biology beyond bioenergetics support transformation, including mitochondrial biogenesis and turnover, fission and fusion dynamics, cell death susceptibility, oxidative stress regulation, metabolism, and signaling. Thus, understanding mechanisms of mitochondrial function during tumorigenesis will be critical for the next generation of cancer therapeutics.

Copyright © 2016 Elsevier Inc. All rights reserved.

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Figures

Figure 1

Figure 1. Mitochondria and Cancer

The role of mitochondrial metabolism, bioenergetics, mtDNA, oxidative stress regulation, fission and fusion dynamics, cell death regulation, biogenesis and turnover and signaling in tumorigenesis.

Figure 2

Figure 2. Mitochondria and stages of tumorigenesis

Mitochondrial biology supports tumorigenesis at multiple stages. Mutations in mitochondrial enzymes generate oncometabolites that result in tumor initiation. Mitochondrial metabolic reprogramming, oxidative signaling and signaling can promote tumor growth and survival. Mitochondria additionally regulate redox homeostasis, susceptibility to cell death via alterations in morphology to promote cell survival. Alterations in mitochondrial mass via regulation of biogenesis and mitophagy also contribute to survival depending on cancer type. Mitochondrial metabolic reprogramming, biogenesis, redox homeostasis and dynamics also contribute to metastatic potential of cancer cells.

Figure 3

Figure 3. Effects of classical oncogenic and tumor suppressive pathways on mitochondrial biology

Key mechanisms of mitochondrial regulation by c-MYC, K-RAS, PI3K and p53 signaling pathways. Through transcriptional regulation, c-Myc induces mitochondrial biogenesis and metabolism in addition to its stimulation of cell cycle progression and glycolysis. c-Myc promotes mitochondrial fusion and respiration, which can result in increased ROS production and oxidative signaling. Hyperactive PI3K signaling through either PI3K mutation or loss/mutatoin of the PTEN tumor suppressor results in mTOR activation, which is additionally regulated by nutrient availability, to regulate cell growth. mTOR promotes mitochondrial biogenesis both transcriptionally and translationally. Low nutrient conditions that result in a high AMP/ATP ratio result in AMPK activation, which opposes the mTOR pathway. During chronic nutrient deprivation, AMPK can also promote mitochondrial biogenesis to allow for metabolic flexibility. Loss of p53 promotes survival not only via transcriptional regulation of cell death programs but also through direct interactions with Bcl-2 proteins at the mitochondria. p53 can also induce mitochondrial respiration to promote tumorigenesis by allowing for metabolic flexibility. Oncogenic K-Ras mutations result in a coordinated program of mitochondrial regulation, inhibiting respiration through multiple mechanisms as well as promoting mitochondrial fission and mitophagy.

References

    1. Adam J, Hatipoglu E, O’Flaherty L, Ternette N, Sahgal N, Lockstone H, Baban D, Nye E, Stamp GW, Wolhuter K, Stevens M, Fischer R, Carmeliet P, Maxwell PH, Pugh CW, Frizzell N, Soga T, Kessler BM, El-Bahrawy M, Ratcliffe PJ, Pollard PJ. Renal Cyst Formation in Fh1-Deficient Mice Is Independent of the Hif/Phd Pathway: Roles for Fumarate in Keap1 Succination and Nrf2 Signaling. Cancer Cell. 2011;20:524–537. - PMC - PubMed
    1. Aisenberg AC, Reinafarje B, Potter VR. Studies on the Pasteur Effect. I. General Observations. J Biol Chem. 1957;224:1099–1113. - PubMed
    1. Bause AS, Haigis MC. Sirt3 Regulation of Mitochondrial Oxidative Stress. Exp Gerontol. 2013;48:634–639. - PubMed
    1. Bell EL, Emerling BM, Ricoult SJ, Guarente L. Sirt3 Suppresses Hypoxia Inducible Factor 1alpha and Tumor Growth by Inhibiting Mitochondrial Ros Production. Oncogene. 2011;30:2986–2996. - PMC - PubMed
    1. Ben-Sahra I, Hoxhaj G, Ricoult SJ, Asara JM, Manning BD. Mtorc1 Induces Purine Synthesis through Control of the Mitochondrial Tetrahydrofolate Cycle. Science. 2016;351:728–733. - PMC - PubMed

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