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Ultraviolet (UV) irradiation significantly contributes to photoaging. Ferroptosis, an iron-dependent cell death mode recently identified, plays a key role in UVB-induced skin photoaging. This study examines the functions and regulatory mechanisms of ferroptosis in this regard. Characterized by increased intracellular iron and reactive oxygen species (ROS), ferroptosis is associated with mitochondrial function and structure. Through RNA sequencing, we identified NADH: ubiquinone oxidoreductase subunit S4 (NDUFS4), a gene implicated in UVB-mediated photoaging, and explored its role in ferroptosis by NDUFS4 knockdown. In vitro, inhibiting NDUFS4 reduced ferroptosis, decreased ROS and matrix metallopeptidase 1 levels, and increased collagen type I alpha 1 chain, glutathione peroxidase 4 (GPX4), ferritin heavy chain 1, and solute carrier family 7 member 11 levels, suggesting a reinforced ferroptosis protective mechanism. Additionally, NDUFS4 regulates ferroptosis via the mitogen-activated protein kinase (MAPK) pathway, with its knockdown reducing p38 and ERK phosphorylation and elevating GPX4 levels, enhancing ferroptosis resistance. Animal experiments supported these findings, demonstrating that Ferrostatin-1, a ferroptosis inhibitor, significantly mitigated UVB-induced skin photoaging and related protein expression. This study uncovers NDUFS4's novel role in regulating ferroptosis and provides new insights into ferroptosis-mediated UVB-induced skin photoaging.

Background Eurasian pigs have undergone lineage admixture throughout history. It has been confirmed that the genes of indigenous pig breeds in China have been introduced into Western commercial pigs, providing genetic materials for breeding Western pigs. Pigs in Taihu Lake region (TL), such as the Meishan pig and Erhualian pig, serve as typical representatives of indigenous pig breeds in China due to their high reproductive performances. These pigs have also been imported into European countries in 1970 and 1980 s. They have played a positive role in improving the reproductive performances in European commercial pigs such as French Large White pigs (FLW). However, it is currently unclear if the lineage of TL pigs have been introgressed into the Danish Large White pigs (DLW), which are also known for their high reproductive performances in European pigs. To systematically identify genomic regions in which TL pigs have introgressed into DLW pigs and their physiological functions, we collected the re-sequencing data from 304 Eurasian pigs, to identify shared haplotypes between DLW and TL pigs. Results The findings revealed the presence of introgressed genomic regions from TL pigs in the genome of DLW pigs indeed. The genes annotated within these regions were found to be mainly enriched in neurodevelopmental pathways. Furthermore, we found that the 115 kb region located in SSC16 exhibited highly shared haplotypes between TL and DLW pigs. The major haplotype of TL pigs in this region could significantly improve reproductive performances in various pig populations. Around this genomic region, NDUFS4 gene was highly expressed and showed differential expression in multiple reproductive tissues between extremely high and low farrowing Erhualian pigs. This suggested that NDUFS4 gene could be an important candidate causal gene responsible for affecting the reproductive performances of DLW pigs. Conclusions Our study has furthered our knowledge of the pattern of introgression from TL into DLW pigs and the potential effects on the fertility of DLW pigs.

Increasing evidence demonstrate that the electron transfer chain plays a critical role in controlling the effector functions of macrophages. In this work, we have generated a Ndufs4 −/− murine macrophage cell lines. The Ndufs4 gene, which encodes a supernumerary subunit of complex I, is a mutational hotspot in Leigh syndrome patients. Ndufs4 −/− macrophages showed decreased complex I activity, altered complex I assembly, and lower levels of maximal respiration and ATP production. These mitochondrial respiration alterations were associated with a shift towards a pro-inflammatory cytokine profile after lipopolysaccharide challenge and improved ability to phagocytose Gram-negative bacteria.

Reduction of mitochondrial complex I activity is one of the major hypotheses for dopaminergic neuron death in Parkinson’s disease. However, reduction of complex I activity in all cells or selectively in dopaminergic neurons via conditional deletion of the Ndufs4 gene, a subunit of the mitochondrial complex I, does not cause dopaminergic neuron death or motor impairment. Here, we investigated the effect of reduced complex I activity on non-motor symptoms associated with Parkinson’s disease using conditional knockout (cKO) mice in which Ndufs4 was selectively deleted in dopaminergic neurons ( Ndufs4 cKO). This conditional deletion of Ndufs4, which reduces complex I activity in dopamine neurons, did not cause a significant loss of dopaminergic neurons in substantia nigra pars compacta (SNpc), and there was no loss of dopaminergic neurites in striatum or amygdala. However, Ndufs4 cKO mice had a reduced amount of dopamine in the brain compared to control mice. Furthermore, even though motor behavior were not affected, Ndufs4 cKO mice showed non-motor symptoms experienced by many Parkinson’s disease patients including impaired cognitive function and increased anxiety-like behavior. These data suggest that mitochondrial complex I dysfunction in dopaminergic neurons promotes non-motor symptoms of Parkinson’s disease and reduces dopamine content in the absence of dopamine neuron loss.

Anesthetics are in routine use, yet the mechanisms underlying their function are incompletely understood. Studies in vitro demonstrate that both GABA(A) and NMDA receptors are modulated by anesthetics, but whole animal models have not supported the role of these receptors as sole effectors of general anesthesia. Findings in C. elegans and in children reveal that defects in mitochondrial complex I can cause hypersensitivity to volatile anesthetics. Here, we tested a knockout (KO) mouse with reduced complex I function due to inactivation of the Ndufs4 gene, which encodes one of the subunits of complex I. We tested these KO mice with two volatile and two non-volatile anesthetics. KO and wild-type (WT) mice were anesthetized with isoflurane, halothane, propofol or ketamine at post-natal (PN) days 23 to 27, and tested for loss of response to tail clamp (isoflurane and halothane) or loss of righting reflex (propofol and ketamine). KO mice were 2.5 - to 3-fold more sensitive to isoflurane and halothane than WT mice. KO mice were 2-fold more sensitive to propofol but resistant to ketamine. These changes in anesthetic sensitivity are the largest recorded in a mammal.

Mitochondrial complex I, the primary entry point for electrons into the mitochondrial respiratory chain, is both critical for aerobic respiration and a major source of reactive oxygen species. In the heart, chronic dysfunction driving cardiomyopathy is frequently associated with decreased complex I activity, from both genetic and environmental causes. To examine the functional relationship between complex I disruption and cardiac dysfunction we used an established mouse model of mild and chronic complex I inhibition through heart-specific Ndufs4 gene ablation. Heart-specific Ndufs4-null mice had a decrease of ∼ 50% in complex I activity within the heart, and developed severe hypertrophic cardiomyopathy as assessed by magnetic resonance imaging. The decrease in complex I activity, and associated cardiac dysfunction, occurred absent an increase in mitochondrial hydrogen peroxide levels in vivo, accumulation of markers of oxidative damage, induction of apoptosis, or tissue fibrosis. Taken together, these results indicate that diminished complex I activity in the heart alone is sufficient to drive hypertrophic cardiomyopathy independently of alterations in levels of mitochondrial hydrogen peroxide or oxidative damage.

The gene encodes an 18-kD subunit of mitochondria complex I, and mutations in this gene lead to the development of a severe neurodegenerative disease called Leigh syndrome (LS) in humans. To investigate the disease phenotypes and molecular mechanisms of Leigh syndrome, the knockout (KO) mouse has been widely used as a novel animal model. Because the homozygotes cannot survive beyond child-bearing age, whether and mitochondrial complex I influence early embryonic development remains unknown. In our study, we attempted to investigate embryonic development in KO mice, which can be regarded as a Leigh disease model and were created through the CRISPR (clustered regularly interspaced short palindromic repeat) and Cas9 (CRISPR associated)-mediated genome editing system. We first designed a single guide RNA (sgRNA) targeting exon 2 of to delete the NDUFS4 protein in mouse embryos to mimic Leigh syndrome. Then, we described the phenotypes of our mouse model by forced swimming and the open-field test as well as by assessing other behavioral characteristics. Intracytoplasmic sperm injection (ICSI) was performed to obtain KO embryos to test the influence of NDUFS4 deletion on early embryonic development. In this study, we first generated KO mice with physical and behavioral phenotypes similar to Leigh syndrome using the CRISPR/Cas9 system. The low developmental rate of KO embryos that were derived from knockout gametes indicated that the absence of NDUFS4 impaired the development of preimplantation embryos. In this paper, we first obtained KO mice that could mimic Leigh syndrome using the CRISPR/Cas9 system. Then, we identified the role of NDUFS4 in early embryonic development, shedding light on its roles in the respiratory chain and fertility. Our model provides a useful tool with which to investigate the function of . Although the pathological mechanisms of the disease need to be discovered, it helps to understand the pathogenesis of NDUFS4 deficiency in mice and its effects on human diseases.

We report a patient with complex clinical presentation including multiple neurological symptoms and eye involvement. Upon genetic investigation, the patient was found to carry a novel homozygous mutation in the NDUFS4 gene, thus adding to the heterogeneity of Leigh syndrome clinical presentation. We report a patient with complex clinical presentation including multiple neurological symptoms and eye involvement. Upon genetic investigation, the patient was found to carry a novel homozygous mutation in the NDUFS4 gene, thus adding to the heterogeneity of Leigh syndrome clinical presentation.

To study the molecular basis of intramuscular fat (IMF) deposition, suppression subtractive hybridization was used to investigate the differences in gene expression between m. longissimus dorsi (LD) of high IMF Laiwu pig group and low IMF Laiwu pig group. From two specific subtractive cDNA libraries, the expression-upregulated clone HL-27 was selected by reverse Northern high-density blot, and then identified to be pig mitochondrial NADH dehydrogenase (ubiquinone) Fe-S protein 4 (NDUFS4). Pig NDUFS4 full-length cDNA was cloned by RACE, and contains a 528 bp-open reading frame (ORF) encoding 175 amino acid residues. The derived amino acid sequence of NDUFS4 is well conserved compared with NDUFS4 of various species with higher degree of sequence similarity with other mammalian (86.3–92.6 %) than amphibian, aves, and fishes (70.2–81.1 %), and contains one N-linked glycosylation site, one O-linked glycosylation site, seven Ser phosphorylation sites and five Thr phosphorylation sites. A-G mutation was found at nt 122 site of ORF between Laiwu pig and Large White, which results in the K-R mutation at 41 site of protein sequence. Real-time PCR analysis indicated that the level of NDUFS4 mRNA expression was higher in high IMF Laiwu pig group than in low IMF Laiwu pig group, and in Laiwu pig than in Large White. The tissue expression of the pig NDUFS4 gene showed a tissue-specific pattern: highly expressed in LD muscle, spleen and kidney, but hardly expressed in lung, stomach and large intestine. The possible role of NDUFS4 and its relation to IMF deposition are discussed.

Complex I deficiency, the most common cause of mitochondrial disorders, accounts for a variety of clinical symptoms and its genetic heterogeneity makes identification of the disease genes particularly tedious. Indeed, most of the 43 complex I subunits are encoded by nuclear genes, only seven of them being mitochondrially encoded. In order to offer urgent prenatal diagnosis, we have studied an inbred/multiplex family with complex I deficiency by using microsatellite DNA markers flanking the putative disease loci. Microsatellite DNA markers have allowed us to exclude the NDUFS7, NDUFS8, NDUFV1 and NDUFS1 genes and to find homozygosity at the NDUFS4 locus. Direct sequencing has led to identification of a homozygous splice acceptor site mutation in intron 1 of the NDUFS4 gene (IVS1nt -1, G-->A); this was not found in chorion villi of the ongoing pregnancy. We suggest that genotyping microsatellite DNA markers at putative disease loci in inbred/multiplex families helps to identify the disease-causing mutation. More generally, we suggest giving consideration to a more systematic microsatellite analysis of putative disease loci for identification of disease genes in inbred/multiplex families affected with genetically heterogeneous conditions.