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Review
. 2021 Nov 3:2021:1341604.
doi: 10.1155/2021/1341604. eCollection 2021.

Interplay between Mitochondrial Metabolism and Cellular Redox State Dictates Cancer Cell Survival

Brittney Joy-Anne Foo  1 , Jie Qing Eu  1   2 , Jayshree L Hirpara  2 , Shazib Pervaiz  1   3   4   5   6   7
Affiliations
Review

Interplay between Mitochondrial Metabolism and Cellular Redox State Dictates Cancer Cell Survival

Brittney Joy-Anne Foo et al. Oxid Med Cell Longev. .

Abstract

Mitochondria are the main powerhouse of the cell, generating ATP through the tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS), which drives myriad cellular processes. In addition to their role in maintaining bioenergetic homeostasis, changes in mitochondrial metabolism, permeability, and morphology are critical in cell fate decisions and determination. Notably, mitochondrial respiration coupled with the passage of electrons through the electron transport chain (ETC) set up a potential source of reactive oxygen species (ROS). While low to moderate increase in intracellular ROS serves as secondary messenger, an overwhelming increase as a result of either increased production and/or deficient antioxidant defenses is detrimental to biomolecules, cells, and tissues. Since ROS and mitochondria both regulate cell fate, attention has been drawn to their involvement in the various processes of carcinogenesis. To that end, the link between a prooxidant milieu and cell survival and proliferation as well as a switch to mitochondrial OXPHOS associated with recalcitrant cancers provide testimony for the remarkable metabolic plasticity as an important hallmark of cancers. In this review, the regulation of cell redox status by mitochondrial metabolism and its implications for cancer cell fate will be discussed followed by the significance of mitochondria-targeted therapies for cancer.

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Conflict of interest statement

The authors declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1
Regulation of carcinogenesis by ROS. At different ROS levels, cells experience a dichotomous fate. Moderate and low ROS levels tend to promote cell growth and uncontrolled proliferation, thus, promoting carcinogenesis and/or its progression. On the other end of the spectrum, high ROS levels tip the balance to cell death, preventing further growth of the tumor. Figure created with biorender.com.
Figure 2
Figure 2
ROS regulation of signaling pathways in cancer. ROS has been demonstrated to regulate signaling pathways in cancer. Increase in ROS such as H2O2 activates PI3K/Akt signaling pathway through the inhibition of PTEN, resulting in constitutive activation of PI3K/Akt that contributes to cell survival and proliferation in cancer. Similarly, ASK-1, a kinase in the MAPK signaling cascade, is displaced from Trx-ASK1 complex under oxidative stress. ASK-1 subsequently activates downstream p38 and JNK, leading to apoptosis and autophagy. Redox-mediated inactivation of PP2A was reported to sustain NF-κB activation, Bcl-2 phosphorylation at Ser70, and Myc phosphorylation at Ser62, leading to cell migration and invasion, inhibition of DNA damage and cell proliferation, respectively. Figure created with biorender.com.
Figure 3
Figure 3
Nuclear-encoded and mitochondrial-encoded mitochondria regulatory genes are susceptible to oxidative damage. Nuclear-encoded mitochondrial genes such as SDH, which makes up complex II of the ETC, are assembled and transported into the mitochondria and susceptible to inactivation by ROS such as H2O2. In addition, FH generates energy for the cells by converting fumarate into malate in the TCA cycle, and SUV3 is a nuclear-encoded ATP-dependent DNA/RNA helicase and function as a tumor suppressor. The mtDNA encodes for subunits of the ETC and regulatory proteins that are important for the assembly and function of the ETC. The mtDNA is highly susceptible to oxidative stress-induced damage, leading to OXPHOS dysregulation. Figure created with biorender.com.
Figure 4
Figure 4
Mitochondrial-directed therapeutic strategies. For drugs that target the mitochondrial matrix, components of the electron transport chain and MnSOD are mainly affected, whereas drugs targeting cytosolic regulatory proteins/factors such as the balance between the pro- and antiapoptotic members of the Bcl-2 family affect apoptotic execution. Figure created with biorender.com.
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