The Oncojanus Paradigm of Respiratory Complex I.

Giulia Leone,Giuseppe Gasparre,Luisa Iommarini,Houda Abla,Anna Porcelli

doi:10.3390/genes9050243

Giulia Leone, Giuseppe Gasparre + Show 3 more

Open Access

https://doi.org/10.3390/genes9050243

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Abstract

Mitochondrial respiratory function is now recognized as a pivotal player in all the aspects of cancer biology, from tumorigenesis to aggressiveness and chemotherapy resistance. Among the enzymes that compose the respiratory chain, by contributing to energy production, redox equilibrium and oxidative stress, complex I assumes a central role. Complex I defects may arise from mutations in mitochondrial or nuclear DNA, in both structural genes or assembly factors, from alteration of the expression levels of its subunits, or from drug exposure. Since cancer cells have a high-energy demand and require macromolecules for proliferation, it is not surprising that severe complex I defects, caused either by mutations or treatment with specific inhibitors, prevent tumor progression, while contributing to resistance to certain chemotherapeutic agents. On the other hand, enhanced oxidative stress due to mild complex I dysfunction drives an opposite phenotype, as it stimulates cancer cell proliferation and invasiveness. We here review the current knowledge on the contribution of respiratory complex I to cancer biology, highlighting the double-edged role of this metabolic enzyme in tumor progression, metastasis formation, and response to chemotherapy.

Highlights

The mitochondrial oxidative phosphorylation (OXPHOS) system is the major site of energy production in eukaryotic cells and is composed of four respiratory complexes and Fo F1 –adenosine triphosphate (ATP) synthase organized in functional supramolecular structures, such as dimers of single complexes or supercomplexes formed by the association of different complexes [1]
An increasing number of studies have highlighted the pivotal role of the mitochondrial OXPHOS system and, in particular, of complex I (CI) in all aspects of cancer biology
The first studies reported that CI impairment was associated with increased tumorigenic properties of cancer cells, but it has been found that the severity of CI dysfunction strongly influences tumor progression, metastasis formation, and resistance to certain chemotherapeutics (Figure 4)

Summary

Introduction

The mitochondrial oxidative phosphorylation (OXPHOS) system is the major site of energy production in eukaryotic cells and is composed of four respiratory complexes (complex I, II, III, and IV) and Fo F1 –adenosine triphosphate (ATP) synthase organized in functional supramolecular structures, such as dimers of single complexes or supercomplexes formed by the association of different complexes [1] Among these enzymatic giants, respiratory complex I (CI) ( referred to as nicotinamide adenine dinucleotide (NADH): ubiquinone oxidoreductase/EC.1.6.5.3) is the largest, being composed of 44 subunits, seven of which (ND1–6 and ND4L) are encoded by mitochondrial DNA (mtDNA). The functional significance of genetic and transcriptional alterations of CI genes, in both nDNA- and mtDNA-encoded subunits, has been investigated, leading to several hypotheses regarding their selection and accumulation in cancer and their role in tumor progression, metastasis formation, and resistance to chemotherapy (Figure 1B,C). Amino acid substitutions induced by missense mutations reported in the text and involved in tumor biology are shown as spheres and are colored red

Mitochondrial DNA Features and Genetics

Complex I as a Target for Anti-Cancer Therapy?

Findings

Concluding Remarks