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Review
. 2020 Aug 5;21(16):5598.
doi: 10.3390/ijms21165598.

The Significance of Mitochondrial Dysfunction in Cancer

Yongde Luo  1   2 , Jianjia Ma  2 , Weiqin Lu  2
Affiliations
Review

The Significance of Mitochondrial Dysfunction in Cancer

Yongde Luo et al. Int J Mol Sci. .

Abstract

As an essential organelle in nucleated eukaryotic cells, mitochondria play a central role in energy metabolism, maintenance of redox balance, and regulation of apoptosis. Mitochondrial dysfunction, either due to the TCA cycle enzyme defects, mitochondrial DNA genetic mutations, defective mitochondrial electron transport chain, oxidative stress, or aberrant oncogene and tumor suppressor signaling, has been observed in a wide spectrum of human cancers. In this review, we summarize mitochondrial dysfunction induced by these alterations that promote human cancers.

Keywords: TCA cycle; cancers; dysfunction; electron transport chain; mitochondria; oncogene; oxidative phosphorylation; tumor suppressor.

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Conflict of interest statement

The authors declare no potential conflict of interest.

Figures

Figure 1
Figure 1
Dysfunctional tricarboxylic acid (TCA) cycle enzymes in cancers. The normal TCA cycle deemed for the breakdown of acetyl-CoA is subject to disruption by oxidative stress and dysfunction of the TCA cycle enzymes, contributing to various cancers. Mutations in IDH2 can lead to the production of D-2HG from α-KG. Abnormal accumulation of 2-HG causes epigenetic landscape alterations and inhibits SDH, resulting in the accumulation of succinyl-CoA and mitochondrial respiration impairment. Mutations in SDH cause abnormal accumulation of succinate and subsequent inhibition of PHDs, resulting in HIF1a stabilization. Like SDH, mutations in FH also cause HIF1a stabilization. Oxidative stress induced by the dysfunction of mitochondrial electron transport chain causes abnormal modification of the iron-sulfur center in aconitase, leading to the exportation of citrate from mitochondria for cholesterol and fatty acid synthesis. All of these abnormal alterations in the TCA cycles have been more or less implicated in neoplastic transformation of different types at different degrees. PDH, pyruvate dehydrogenase. PHD, HIF prolyl hydroxylase. D-2HG, D enantiomer of 2-hydroxyglutarate. α-KG, alpha-ketoglutarate. IDH, isocitrate dehydrogenase. SDH, succinate dehydrogenase. FH, fumarate hydratase.
Figure 2
Figure 2
Mitochondrial genome, electron transport chain, and oxidative stress in cancer development. Mitochondria have their own supercoiled, double-stranded genome called mtDNA. Polymerase gamma (POLG) is the only polymerase responsible for mtDNA replication. Mitochondrial transcription factor A (TFAM) is responsible for mtDNA transcription. The products of mtDNA translation are all involved in the assembly of the mitochondrial respiratory chain, including complex I, complex III, complex IV, and complex V, while all components of complex II are encoded by nuclear DNA. NADH as a product of the TCA cycle feeds into complex I, while succinate as a substrate feeds into complex II of the electron transport chain. Electron leakage from complex I and III can be captured by molecule oxygen to generate superoxide (O2−), which may lead to oxidative stress. Mitochondrial dysfunction can also enhance NADPH oxidase (NOX) activity for the generation of O2−. SODs can convert O2− to H2O2, which can be then converted to other forms of ROS. ROS can act as a second messenger to alter normal signaling cascades, or directly damage DNAs, proteins, and lipids, thus inducing genomic instability, redox imbalance, and the development of cancers and drug resistance.
Figure 3
Figure 3
Schematic of mitochondrial electron transport chain and oxidative phosphorylation system. In mammalian cell mitochondria, the oxidative phosphorylation system (OXPHOS) is located largely across the inner membrane and on the side of the matrix and is organized into five multi-enzyme complexes, including complex I (also called NADH dehydrogenase), complex II (Succinate dehydrogenase), complex III (cytochrome bc1 complex or CoQ-Cyt c oxidoreductase), complex IV or cyt c oxidase (CO), and complex V (FoF1-ATP synthase) for oxidative phosphorylation and energy transfer to ATP. The high-energy electron carriers NADH and FADH2 produced by the intermediate substrate metabolism in the TCA cycle in the matrix are sequentially oxidized by Complex I and II to generate an electrochemical proton gradient across the inner membrane, which is eventually used as a driving force by the Complex V to produce ATP. FMN, flavin mononucleotide. Fe-S, iron-sulfur cluster at enzyme center. e-, a high-energy electron of negative charge. CoQ, ubiquinone or coenzyme Q. CoQH2, reduced coenzyme Q or ubiquinol. Cyt, cytochrome. CuA, cupper-containing metallic center A of complex IV. Heme a, heme-containing cytochrome a. A, B, C, α, β, γ, δ, and ε, different protein subunits of complex V. Pi, inorganic phosphate ion.
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