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Review
. 2022 Dec 9;27(24):8754.
doi: 10.3390/molecules27248754.

Emerging Roles of NDUFS8 Located in Mitochondrial Complex I in Different Diseases

Sifan Wang  1   2   3   4   5 , Yuanbo Kang  1   2   3   4   5 , Ruifeng Wang  1   2 , Junqi Deng  1   2 , Yupei Yu  1   2 , Jun Yu  6 , Junpu Wang  1   2   3   4
Affiliations
Review

Emerging Roles of NDUFS8 Located in Mitochondrial Complex I in Different Diseases

Sifan Wang et al. Molecules. .

Abstract

NADH:ubiquinone oxidoreductase core subunit S8 (NDUFS8) is an essential core subunit and component of the iron-sulfur (FeS) fragment of mitochondrial complex I directly involved in the electron transfer process and energy metabolism. Pathogenic variants of the NDUFS8 are relevant to infantile-onset and severe diseases, including Leigh syndrome, cancer, and diabetes mellitus. With over 1000 nuclear genes potentially causing a mitochondrial disorder, the current diagnostic approach requires targeted molecular analysis, guided by a combination of clinical and biochemical features. Currently, there are only several studies on pathogenic variants of the NDUFS8 in Leigh syndrome, and a lack of literature on its precise mechanism in cancer and diabetes mellitus exists. Therefore, NDUFS8-related diseases should be extensively explored and precisely diagnosed at the molecular level with the application of next-generation sequencing technologies. A more distinct comprehension will be needed to shed light on NDUFS8 and its related diseases for further research. In this review, a comprehensive summary of the current knowledge about NDUFS8 structural function, its pathogenic mutations in Leigh syndrome, as well as its underlying roles in cancer and diabetes mellitus is provided, offering potential pathogenesis, progress, and therapeutic target of different diseases. We also put forward some problems and solutions for the following investigations.

Keywords: Leigh syndrome; NDUFS8; cancer; diabetes mellitus; metabolism; mitochondrial complex I.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Location, structure, functional mechanism, and clinical pathogenic variants of NDUFS8. (A) Cryo-EM structure of human respiratory complex I (CI) with other subunits in grey from 5XTD (EMD-6773) [8]. The ribbon highlighted in green represents NDUFS8. (B) The folds of NDUFS8 are shown in ribbon representation. NDUFS8 contains two [4Fe–4S]2+/1+ clusters represented by a combination of red and yellow balls. The pathogenic mutation sites of NDUFS8 are presented by magenta balls. (C) Schematic representation of components and functions of CI. CI consists of three functional modules: NADH oxidation (N module), ubiquinone reduction (Q module), and proton translocation (P module). They form an L-shape: one hydrophobic arm oriented parallel to the membrane and a hydrophilic arm extending into the mitochondrial matrix. There is a chain of seven FeS clusters that can transfer electrons from FMN to the ubiquinone reduction site. The P module harbors proton-translocation pathways connecting the mitochondrial matrix and the intermembrane space. (D) NDUFS8 (blue), NDUFS1 (pink), NDUFS2 (green), NDUFS7 (grey), and NDUFA12 (yellow) of complex I are shown. The annotated pathogenic mutation residues probably have effects on NDUFS8 and its surroundings, leading to complex I dysfunction [28]. Among them, p.Cys153Arg, p.Gly154Ser, and p.Val162Met are associated with the surroundings of two [4Fe–4S]2+/1+ clusters in NDUFS8, possibly disrupting electron transfer. The p.Ala159Asp lies next to Cys126, a component of the surroundings of two [4Fe–4S]2+/1+ clusters in NDUFS8. The p.Arg138His is linked to the disruption of electron transfer at the N5 cluster in NDUFS1. Moreover, the p.Arg94Cys is responsible for the impaired interaction of NDUFS8 and NDUFS2, while the p.Pro85Leu is associated with the impaired interaction of NDUFS8, NDUFA12, and NDUFS7. Abbreviations: NDUFS8: NADH:ubiquinone oxidoreductase core subunit S8; NDUFA12: NADH:ubiquinone oxidoreductase subunit A12; FMN: flavine mononucleotide; CI: complex I; NADH: Nicotinamide adenine dinucleotide; Q: ubiquinone.
Figure 2
Figure 2
The roles of NDUFS8 in cancers. Several cancerogenic factors, such as oxidative stress, hypoxia, and DNA damage stress upregulate the level of mitochondrial Lon. Then, the elevated expression of NDUFS8 via the mitochondrial Lon caused an increased level of ROS in mitochondria [62]. Increased ROS concentration in tumor cells improves cell survival, proliferation, transformation, and migration through the activation of Ras-ERK1/2 signaling [78], STATs, and/or p38/JNK [62]. Meanwhile, the expression of NDUFS8 shows a strong positive correlation with GPX4 expression linked to tumorigenesis [79]. Moreover, induced by the E2/ER pathway [80], the general transcription factors NRF1/2, Sp1, and YY1 can activate the transcription of NDUFS8. LYRM4 [81], long non-coding RNA PPP1R14B-AS1 [82], and decitabine [83] can also increase NDUFS8 expression in some cancer cells. Abbreviations: NDUFS8: NADH:ubiquinone oxidoreductase core subunit S8; ROS: Reactive Oxygen Species; GPX4: Glutathione peroxidase 4; EMT: epithelial–mesenchymal transition; MEK1/2: mitogen-activated protein kinase kinases 1/2; ERK1/2: extracellular signal-regulated kinase 1/2; STATs: signal transducers and activators of transcription; JNK: c-Jun N-terminal kinase; E2: estrogen; ER: estrogen receptor; NRF1/2: nuclear respiratory factor 1/2; Sp1: Specificity Protein 1; YY1: Yin Yang 1; LYRM4: LYR (leucine/tyrosine/arginine) motif protein 4.
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