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NDUFS8 in Diseases: Comparison
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Please note this is a comparison between Version 2 by Jason Zhu and Version 1 by Junpu Wang.

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 diagnostic approach requires targeted molecular analysis, guided by a combination of clinical and biochemical features.

  • NDUFS8
  • mitochondrial complex I
  • Leigh syndrome

1. Introduction

Mitochondria in eukaryotes play a vital role in bioenergetics, metabolism, as well as signal transduction, and are related to various diseases [1]. Mitochondria contain at least 1500 different proteins in humans, functioning as core parts in energy metabolism, the fusion and fission of mitochondria, and the regulation of cell function [1,2][1][2]. From 20 to 25% of these proteins were used to express, regulate, and maintain the mitochondrial genome that codes for only 1% of mitochondrial proteins, and only up to 15% were directly involved in energy metabolism [3]. About 99% of mitochondrial proteins are encoded by nuclear genes, synthesized in the cytosol, and directed onto the membrane and then into the subcompartments of mitochondria by different signal pathways [4]. The invaginations of the mitochondrial inner membrane contain the respiratory complexes I to IV and the F1F0-ATP synthase, which constitute the oxidative phosphorylation system [1].
Mitochondrial complex I is also named mitochondrial NADH: ubiquinone oxidoreductase is the largest multi-subunit enzyme of the mitochondrial respiratory chain with 38 nuclear-encoded subunits and 7 subunits encoded by the mitochondrial genome [5]. Mitochondrial complex I, the initial and key limiting enzyme, can catalyze the transfer of electrons from Nicotinamide adenine dinucleotide (NADH) to ubiquinone through the respiratory chain, whose changes in the structure and function lead to wide varieties of clinical syndromes ranging from lethal encephalopathies to neurodegenerative disorders [6,7][6][7]. Complex I also consists of the I–III–IV supercomplexes, which may coordinate the activity of respiratory complexes, affect the assembly and stability of the complexes, and/or reduce the formation of reactive oxygen species (ROS) [8].
NADH:ubiquinone oxidoreductase core subunit S8 (NDUFS8), also called TYKY, is a nuclear-encoded subunit of human mitochondrial complex I with a molecular size of about 23 kDa. NDUFS8 is one of the core subunits of complex I, directly involved in the electron transfer process catalyzed by complex I owing to its special structure of containing tetranuclear FeS clusters (N6a and N6b) [9,10][9][10]. Based on this, pathogenic variants of the NDUFS8 are relevant to infantile-onset and severe diseases, including Leigh syndrome, cancer, and diabetes mellitus [6,9][6][9].

2. Pathogenic Variants of the NDUFS8 and Leigh Syndrome

Complex I deficiency caused by complex I gene mutation is highly relevant to mitochondrial disorders, leading to neuromuscular symptoms and various clinical manifestations [39][11]. Among them, Leigh syndrome (LS, OMIM: 256000) is the most common pediatric presentation of the mitochondrial disorder [40][12]. Typically first seen before 12 months of age, LS was first described by Denis Leigh in 1951 and characterized by focal, bilaterally symmetrical, and subacute necrotic lesions in the brainstem, the thalamus, and the posterior columns of the spinal cord [41][13]. Devastatingly, this neurodegenerative disorder is both phenotypically and genetically heterogeneous, and so far, pathogenic mutations in more than 75 genes have been proven, encoded by nuclear and mitochondrial genomes, especially the mutations referring to the mitochondrial respiratory enzyme complex or pyruvate dehydrogenase complex [40,42,43][12][14][15]. To date, mitochondrial complex I deficiency is the most common biochemical cause of LS, nearly constituting one-third of its etiology [40][12], and pathogenic variants of the NDUFS8 can be responsible for LS, including homozygous (c.236C > T/p.Pro79Leu, c.460G > A/p.Gly154Ser, c.187G > C/p.Glu63Gln, c.160C > T/p.Arg54Trp, c.281C > T het/p.Arg94Cys) and compound heterozygous (c.236C > T/p.Pro79Leu and c.305G > A/p.Arg102His, c.254C > T/p.Pro85Leu and c.413G > A/p.Arg138His, c.229C > T/p.Arg77Trp and c.476C > A/p.Ala159Asp, c.52C > T/p.Arg18Cys, c.484G > T/p.Val162Met, c.457T > C/p.Cys153Arg) variations in NDUFS8 [6,44,45,46][6][16][17][18]. These pathogenic variations influence assembly of complex I not only because of the misfolding of NDUFS8 but also owing to impaired interaction of other subunits and NDUFS8 [28][19]. Among them, c.236C > T/p.Pro79Leu and c.305G > A/p.Arg102His along with c.364G > A in the NDUFS7 gene have successfully been reconstructed by using the obligate aerobic yeast Yarrowia lipolytica, exhibiting similar complex I defects and possibly sharing their common characteristics in the pathogenesis of LS [47][20]. To date, all identified mutations were missense mutations, and no patients were reported with nonsense mutations in NDUFS8, which suggested that a complete absence of this protein might lead to intrauterine lethality [6]. The clinical manifestations of LS were intricate and manifold and varied from person to person [49][21]. Of the 13 patients, some showed severe manifestations with respiratory problems, feeding difficulties, epilepsy, and hypertrophic cardiomyopathy, and died within three months of life [11,50][22][23]. Others had normal or mildly impaired motor development in the first year of life and developed a slowly progressive neurological disease during childhood, such as slowly progressive muscle weakness, dysarthria, ataxic gait, and severe myopia [6,51][6][24]. According to a study in the Drosophila Model of LS, the severity of manifestations varied possibly depending on the maternally inherited mitochondrial background, and mitochondria–nuclear interactions affected lifespan and neurodegeneration [52][25]. In terms of genetic diagnosis of LS at present, the strategy is rapidly evolving as next-generation sequencing (NGS) technologies, and whole-exome sequencing (WGS), as well as whole-exon sequencing (WES), is becoming available [43,53][15][26]. This will make the molecular diagnosis of LS by screening patients’ genes possible [40][12]. Currently, symptomatic rather than etiological treatments are available for LS, which has been a challenge for researchers [58][27]. With the improvement of therapeutic technology, a cell-penetrating peptide derived from the HIV-1 trans-activator of transcription protein (TAT) has been successfully applied as a carrier to bring fusion proteins into cells without compromising the biological function of the cargoes. Therefore, Lin et al. successfully developed a TAT-mediated protein transduction system to rescue complex I deficiency caused by NDUFS8 defects and proved that treatment with TAT-NDUFS8 not only significantly ameliorated the assembly of complex I in a NDUFS8-deficient cell line but also partially rescued complex I function both in the in-gel activity assay and the oxygen consumption assay [10].

3. NDUFS8 and Cancer

Functional mitochondria are essential for the cancer cell [59][28], and their dysfunction influences the balance of the intracellular environment through complicated signal pathways during cancer oncogenesis and progression [60][29]. Among all mitochondrial biochemical steps, complex I is the first entrance step of oxidative phosphorylation [61][30]. Complex I has also been recognized as one of the main sources of ROS, which is linked to cancer cell survival, proliferation, transformation, and malignancy progression [62,63,64,65][31][32][33][34]. Contrary to the increasing attention to mtDNA mutation in carcinogenesis [66[35][36][37],67,68], the roles of core nuclear-encoded subunits have not yet been much explored, such as NDUFS1, NDUFS2, NDUFS3, NDUFS7, NDUFS8, NDUFV1, and NDUFV2. Among the 7 nuclear-encoded subunits above, the overexpression of NDUFS1 could augment the activity of complex I, reverse glycolysis, and enhance the radiosensitivity of colorectal cancer cells in vivo and in vitro [69][38]. NDUFS2, which impedes anticancer immune surveillance, is the primary target of the antitumor compound SMIP004-7 [70][39]. Not only core subunits but also accessory subunits are highly associated with the biological function of cancer cells. NDUFAF5 is one of the potential targets of NMS-873, which has been verified to reduce drug resistance in colon cancer cells [71][40]. The decrease of micropeptide in mitochondria could promote hepatoma metastasis by enhancing complex I activity, which could be attenuated by knocking down NDUFA7 [72][41]. Likewise, NDUFS8 is involved in carcinogenesis, tumor metabolism, and progression [73][42]. For instance, owing to the upregulation of NDUFS8 mediated by mitochondrial Lon, their overexpression facilitated ROS generation, causing carcinogenesis and progression [62,74,75,76][31][43][44][45]. Meanwhile, deleterious mtDNA mutations were able to increase ROS, providing a proliferative advantage to cancer [77][46]. Studies verified that high NDUFS8 and low NDUFS1 expressions were correlated with poor prognosis in patients and played a leading prognostic role in non-small-cell lung cancer (NSCLC), suggesting that their expressions might predict lung cancer prognosis [73,84][42][47]. This result could be possibly explained due to their different locations in mitochondria. NDUFS8 is located within the Q-module involved in the early steps of respiratory complex I (CI) assembly, while NDUFS1 is located within the N-module incorporated in the last step [37][48]. In this frame, reduced expression of Q-module subunits might have a more severe impact on the CI function than the N-module [73,85][42][49]. Consistent with high NDUFS8 expressions in NSCLC linking significantly reduced overall survival, studies suggested using mitochondrial markers as companion diagnostics in NSCLC patients, which was considerable for treatment stratification and personalized medicine [86][50]. For instance, a study found that NDUFS8 was one of the targets for the treatment of cyclopamine tartrate in NSCLC [87][51]. The elevated NDUFS8 could also be found in hepatocellular carcinoma (HCC) [81][52], which was associated with the dedifferentiation of HCC [88][53]. Likewise, the rise of NDUFS8 in HCC was modulated by LYR (leucine/tyrosine/arginine) motif protein 4 [81][52], helping HCC cells avoid sorafenib and successfully survive [89][54]. A combination of lung adenocarcinoma and liver cancer showed that NDUFS8 was overexpressed as well and positively related to long non-coding RNA PPP1R14B-AS1, promoting tumor cell proliferation and migration via the enhancement of mitochondrial respiration [82][55]. Similarly, according to the survival analysis, the increased expression level of NDUFS8 was associated with poorer overall survival in patients with acute myeloid leukemia (AML). However, how this gene related to the susceptibility and pathogenesis of AML was not extensively examined [79][56]. Recently, a rare NDUFS8 R2C complex I variant in the germline of two AML patients was identified as heterozygous, exhibiting a decreased basal and maximal oxygen consumption rate [90][57]. By testing AML blood samples, 47 genes were annotated within 500 Kb of the association signal and the sentinel variant is a significant expression quantitative trait locus for 12 of these, including NDUFS8 (PBH = 1.69 × 10−4) [91][58]. In breast cells, persistent overstimulation of estrogens and estrogen receptors contributed to the increase of NDUFS8 and ROS, gradually developing estrogen carcinogenesis [80,92][59][60]. Importantly, NDUFS8 has been reported to have an association with tumor relapse in patients with estrogen receptor α-positive breast cancer [93][61]. Despite the pathogenesis described previously, compared to non-TNBC subtypes, NDUFS8 was downregulated in triple-negative breast cancer (TNBCs) with a reduction in mitochondrial respiratory capacity [94,95][62][63]. It has been reported that loss of heterozygosity at chromosome 11q13 existed in up to 70% to 100% of adrenocortical carcinoma (ACC) [96,97][64][65]. NDUFS8 was significantly differentially expressed between benign and malignant adrenocortical tumors (p < 0.05) with an overall accuracy of 87–91%, suggesting that NDUFS8 was a good diagnostic marker for distinguishing ACC from adenoma [98][66]. Based on the underexpression of NDUFS8 in ACC, decitabine, an inhibitor of DNA promoter methylation, recovered the expression of NDUFS8, which revealed a possible role of epigenetic gene silencing in adrenocortical carcinogenesis [83][67]. However, it was uncertain to confirm that NDUFS8 was an independent adverse predictor of shorter overall survival [99][68]. Besides, compared with the normal corresponding tissue, NDUFS8 expression was upregulated in some tumors, such as non-functional pituitary adenoma [100][69], while its expression was significantly decreased in others, such as clear-cell renal cell carcinoma [101][70] and ovarian clear-cell carcinoma [102][71]. However, there were still other cancer models not showing the change in NDUFS8 expression, possibly presenting that dysregulation of NDUFS8 may be specific to a few kinds of cancers [83,88,103,104,105,106][53][67][72][73][74][75]. All in all, research on NDUFS8 expression in cancers is mainly cell experiments and animal models, suggesting different expression levels and impacts in different cancer cells or even unworthiness, and the main mechanism between cancer and NDUFS8 refers to mitochondrial dysfunction but lacks specific evidence [99][68]. Therefore, more extensive studies concerning NDUFS8 in different cancers need to be done with different approaches and aspects. For example, there are more than 50,000 sequenced and accumulated cancer genomes around the world by using WGS, WES, and RNA sequencing (RNA-Seq) [107,108,109][76][77][78]. When it comes to NDUFS8 and cancer, the techniques above, with a whole landscape of driver mutations [110][79], are of great importance to identify whether the NDUFS8 is a structural variant and pathogen of cancer or only the changing levels of NDUFS8 is a symbol of mitochondrial dysfunction.

4. NDUFS8 and Diabetes Mellitus

Diabetes mellitus is one of the metabolic disorders, tightly associated with energy metabolism and mitochondrial function [111,112][80][81]. Some trials have been made in patients with diabetes mellitus, in which they discovered the possible role of NDUFS8 change. It has been found that a higher serum concentration of NDUFS8 was linked to higher insulin sensitivity among people with type 1 diabetes mellitus, which might reflect better mitochondrial function [113][82]. Conversely, the NDUFS8 gene was highly expressed in the skeletal muscle tissue of patients with type 2 diabetes mellitus (T2DM), which might hint that upregulation of NDUFS8 expression would affect the normal glucose metabolism of skeletal muscle tissue, causing insulin resistance and then promoting diabetes. During the formation of T2DM, high glucose, as a strong metabolic stressor, also induced the upregulation of NDUFS8 [115][83]. Additionally, NDUFS8 exhibited increased interaction with insulin receptor substrate 1, which was linked to inflammation-mediated insulin resistance in T2DM patients [116][84]. There was a similar result that showed that NDUFS8 expression was upregulation in high-fat diet-induced obesity-dependent diabetes mouse models, especially in the liver tissue [117][85]. In other studies, some factors, such as Sirtuin 1, leucine, and berberine, could directly or indirectly regulate the expression of the NDUFS8 and then change the secretory pathways and quantity of insulin, suggesting the agent role of NDUFS8 [118,119,120][86][87][88]. Since maternally inherited diabetes and deafness (MIDD) was first described [121][89], many studies on mitochondrial pathogenic variants have appeared successively. Currently, diabetes mellitus has also been reported in mitochondrial diseases caused by autosomal recessive mutations in the nuclear genes mtDNA polymerase gamma (1399G --> A), and mitochondrial inner membrane protein 17 (p.LysMet88-89MetLeu and p.Leu143 *) [122,123][90][91]. The m.14577T > C mutation in MT-ND6, which encodes NADH-ubiquinone oxidoreductase chain 6, a core subunit of complex I, was associated with diabetes mellitus [123][91].

5. NDUFS8 and Other Diseases

Owing to the importance of NDUFS8 in metabolism, it has relations with different diseases. As a vital component of the mitochondrial electron transport chain, expressions of NDUFS8 were detected or knocked out in many studies to reflect mitochondrial function and indicate the underlying mechanism [125,126,127,128,129][92][93][94][95][96]. For example, by measuring expressions of NDUFS8, microRNA-34a accelerated apoptosis of human lens epithelial cells via mitochondrial dysfunction [126][93]. Throughout the progression of sarcopenia, reduced NDUFS8 caused dysregulation of mitochondrial quality control in skeletal muscle in the senescence-accelerated mouse prone 8 [130][97]. The decreased NDUFS8 in sepsis was implicated in oxidative phosphorylation, showing disturbances in energy metabolism [131,132][98][99]. Embryos lacking NDUFS8 displayed the formation of an egg cylinder but lack of gastrulation features in mice, illustrating the initial value of NDUFS8 during the peri-gastrulation [133][100]. Besides, many substances can influence the kidney through NDUFS8. Paraoxonase1 deficiency and hyperhomocysteinemia changed the expression of mouse kidney proteins related to renal diseases, and downregulation of NDUFS8 could account for the involvement of hyperhomocysteinemia and reduced Paraoxonase1 in kidney disease through energy metabolism [134,135][101][102]. In the kidney of lipopolysaccharide-treated animals, NDUFS8 decreased and then led to decreased fatty acids oxidation following lipopolysaccharide treatment [136][103]. Because of the mitochondrial structural disorder after acute kidney injury, the level of NDUFS8 was down about 50%, which was ameliorated by some materials, such as mitochondria-targeted antioxidant Mito-2,2,6,6-tetramethylpiperidine-N-oxyl by injectable self-assembling peptide hydrogel, a novel cyclic helix B peptide, 5-methoxyindole-2-carboxylic acid, and curcumin [137,138,139,140][104][105][106][107]. Interestingly, NDUFS8 played a role in the process that perfusion of isolated rat kidneys with mesenchymal stromal cells/extracellular vesicles prevents ischemic damage, creating a possible application of NDUFS8 in organ transplantation [141][108]. What’s more, a group studied the mitochondrial role in the development of doxorubicin-induced cardiotoxicity and tested a decrease of NDUFS8 in this process, which implicated a possible mechanism of doxorubicin-induced cardiotoxicity [142][109], and similarly, downregulation of the NDUFS8 expression was also involved in the mechanism of Propofol-induced cytotoxicity in human-induced pluripotent stem cell-derived cardiomyocytes [143][110]. Moreover, NDUFS8 can have a relation with neural and psychiatric diseases. Studies showed that chronic stress affected the mitochondrial respiratory chain, and mitochondrial dysfunction might be a potential mechanism of psychiatric pathophysiology [144,145][111][112]. Compared with middle-aged individuals, there were obvious upexpressions of NDUFS8 in the frontal cortex in those with Parkinson’s disease, but notable downexpressions in those with Parkinson’s disease with dementia [146][113]. With the measurement of a significant upregulation of NDUFS8 in the resilient group compared with controls in rat models, it could be speculated that the regulation of this gene protected against stress [147][114]. Additionally, there was an appealing study about an antioxidant fruit named Euterpe oleracea which improved the expression of NDUFS8 to recover rotenone-caused mitochondrial dysfunction in neuronal-like cells SH-SY5Y [148][115].
 

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