Neuroinflammation is involved in the development of depression and may induce depression-like behaviors by affecting metabolism through interactions with circadian rhythms. As the hub of metabolism, mitochondria are regulated by various types of metabolism and release signals that regulate cellular functions. In this study, we performed transcriptomic analysis of the hippocampus of IL-33-overexpressing mice to provide new ideas to explore the pathogenesis of inflammation-mediated depression at the transcriptional level. Male C57BL/6J mice and IL-33-overexpressing mice were subjected to behavioral tests. The hippocampus was extracted during the light or dark period, and differential gene expression analysis was conducted using RNA sequencing. Differential gene enrichment analysis was performed, as well as multilayered analysis of mitochondrial transcriptional rhythms by integrating the regulatory networks and Mito 3.0 database. The results were further verified using RT-qPCR. IL-33-overexpressing mice exhibited depressive behaviors associated with rhythmic disorders and shortened circadian cycles. Differential KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis showed that the top 20 pathways with the lowest p-values included mood-related, immune-related, and circadian rhythm-related pathways. Differential gene GO (Gene Ontology) enrichment analysis showed that 20 of the top 30 pathways with the lowest p-values were related to metabolism. Transcriptome data from IL-33-overexpressing mice showed that the mitochondrial-encoded subunit of the oxidative respiratory complex showed predominantly increased expression during the light period. Metabolic disorders and disrupted mitochondrial transcriptional rhythm were also observed. Weighted gene correlation network analysis showed that the circadian cycle is associated with depression-like behavior disorders. Network analysis showed that circadian-related genes were enriched in mitochondrial pathways related to metabolism and oxidative phosphorylation. Multilayer analysis of mitochondrial transcriptional rhythms using the mitochondrial database Mito 3.0 revealed that mitochondrial dynamics and surveillance pathways were the most enriched. The depressive behavior in mice caused by long-term IL-33 stimulation may be related to changes in the transcriptional rhythms of metabolism-related genes and the interaction between mitochondria and clock genes. This suggests that mitochondrial transcriptional rhythms are central to the pathogenesis of microinflammation-induced depression, further supporting the potential of mitochondria as a target for the prevention and treatment of depression.

Mitochondrial oxidative phosphorylation serves as a critical driving force in the progression of ovarian cancer. Recent studies have demonstrated that copper induces mitochondrial-dependent programmed cell death by directly binding to the thioacylated components of the tricarboxylic acid (TCA) cycle. The involvement of copper in OXPHOS complex IV, a rate-limiting step in the mitochondrial respiratory chain, suggests that the role of mitochondria in mediating copper-induced cell death can be further elucidated through the study of OXPHOS complex IV. The findings of this study indicate that the cuproptosis process in ovarian cancer, induced by Elesclomol, is associated with mitochondrial complex IV, with LRPPRC identified as a crucial factor. Following Elesclomol treatment of ovarian cancer cells, there was a notable increase in mitochondrial reactive oxygen species (ROS), a significant accumulation of the copper death marker protein DLAT, and a marked decrease in the lipoic acid synthesis-related protein FDX1. Furthermore, the expression levels of copper ion transporters ATP7B and CTR1, which are involved in the assembly and translation of complex IV, as well as the core subunit MTCO1 of complex IV, the copper chaperone protein SCO1, and the interacting protein LRPPRC, were significantly diminished. Inhibition of the IV-stabilizing protein LRPPRC in the ovarian cancer cell lines A2780 and SKOV3 through RNA interference resulted in increased sensitivity to Elesclomol. Concurrently, the expression levels of FDX1, LIAS, LIPT1, SCO1, and MTCO1 decreased significantly. These findings suggest that LRPPRC plays a role in inhibiting the expression of lipoic acid and copper chaperone proteins during Elesclomol-induced copper death in ovarian cancer. This inhibition collectively diminishes the expression and activity changes in complex IV, induces mitochondrial dysfunction, and promotes cuproptosis in ovarian cancer. This study further demonstrates that inhibiting the oxidative phosphorylation complex IV can enhance copper-induced cell death in ovarian cancer.

As we age, lens epithelial cells (LECs) undergo various stressors, contributing to cataract development. Targeting the regulation of mitochondrial metabolism may be an effective strategy to delay LEC aging. La-related protein 1 (LARP1) is an RNA-binding protein that affects mitochondrial function by regulating mRNA stability and translation. However, the specific mechanism underlying the role of LARP1 in LEC aging is unclear. In the present study, we found that LARP1 was significantly upregulated during D-galactose-induced senescence in LECs. LARP1 knockdown significantly attenuated cellular senescence and restored mitochondrial oxidative phosphorylation (OXPHOS) function. Further studies revealed that the upregulation of LARP1 inhibited the expression of the nuclear-encoded OXPHOS subunits NDUFB8 and SDHB, thereby impairing OXPHOS function. LARP1 inhibited translation of NDUFB8 and SDHB mRNAs by binding to these mRNAs and forming stress granules (SGs). In the presence of SG inhibitors, the translation levels of NDUFB8 and SDHB were restored, and cellular senescence markers were significantly reduced. In conclusion, the present study revealed the critical role of LARP1 in LEC senescence, suggesting that it impairs mitochondrial OXPHOS function through SG-mediated translational inhibition, which provides new insights into the mechanism of mitochondrial dysfunction in LEC senescence, as well as new intervention strategies to resist LEC senescence.

Aging is closely related to mitochondria, and mitochondrial dysfunction plays an important role in aging, which is also a key cause of degenerative diseases. Mitochondria are essential for maintaining the stability of the intracellular environment, monitoring cellular homeostasis, and can timely reverse transmit stress signals to the nucleus to achieve feedback regulation. Exposure to long-term low-intensity stress stimuli such as reactive oxygen species, accumulation of unfolded proteins, and disruptions of energy metabolism can activate the mitohormesis, triggering a compensatory response in cells to resist stress stimuli and improve cellular resilience, thereby promoting health and prolonging life. In degenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and osteoporosis, the mitohormesis can also be used as potential therapeutic targets. Therefore, it is of great significance to study the mitohormesis to promote health, prolong life, delay aging, and prevent or treat degenerative diseases.

[This corrects the article DOI: 10.3892/ol.2016.4278.].

Targeting the PI3K/mTOR pathway and modulating mitochondrial adaptation is expected to be a critical approach for cancer therapy. Although the regulation of mitochondria by the PI3K/mTOR pathway has been investigated, it is not well understood due to the complexity of its regulatory mechanisms. RNA-binding proteins (RBPs) selectively regulate gene expression through post-transcriptional modulation, playing a key role in cancer progression. LARP1, a downstream RBP of the mTOR pathway, is involved in mitochondria-mediated BCL-2 cell survival. Therefore, exploring the involvement of LARP1 in PI3K/mTOR-mediated translational regulation of mitochondria-associated proteins in ovarian cancer cells could help elucidate the role of mitochondria in the PI3K/mTOR pathway. We found that, unlike SKOV3 cells, the mitochondrial function of A2780 cells was not affected, which were insensitive to the dual PI3K/mTOR inhibitor PKI-402, suggesting that cell survival may be related to mitochondrial function. Knockdown of the LARP1 gene after PKI-402 treatment resulted in impaired mitochondrial function in A2780 cells, possibly due to decreased mRNA stability and reduced protein translation of the mitochondrial transcription initiation factor, TFB2M, and the respiratory chain complex II subunit, SDHB. LARP1 affects protein translation by binding to TFB2M mRNA, regulating mitochondrial DNA-encoded genes, or indirectly regulating the nuclear DNA-encoded SDHB gene, ultimately interfering with mitochondrial oxidative phosphorylation and leading to apoptosis. Therefore, LARP1 may be an important mediator in the PI3K/mTOR pathway for regulating mRNA translation and mitochondrial function. Targeting RBPs such as LARP1 downstream of the mTOR pathway may provide new insights and potential therapeutic approaches for ovarian cancer treatment.

Regeneration and repair are prerequisites for maintaining effective function of skeletal muscle under high energy demands, and myogenic differentiation is one of the key steps in the regeneration and repair process. A striking feature of the process of myogenic differentiation is the alteration of mitochondria in number and function. Mitochondrial dysfunction can activate a number of transcriptional, translational and post-translational programmes and pathways to maintain cellular homeostasis under different types and degrees of stress, either through its own signaling or through constant signaling interactions with the nucleus and cytoplasm, a process known as the mitochondrial stress responses (MSRs). It is now believed that mitochondrial dysfunction is closely associated with a variety of muscle diseases caused by reduced levels of myogenic differentiation, suggesting the possibility that MSRs are involved in messaging during myogenic differentiation. Also, MSRs may be involved in myogenesis by promoting bioenergetic remodeling and assisting myoblast survival during myogenic differentiation. In this review, we will take MSRs as an entry point to explore its concrete regulatory mechanisms during myogenic differentiation, with a perspective to provide a theoretical basis for the treatment and repair of related muscle diseases.

Drug resistance remains a challenge in ovarian cancer. In addition to aberrant activation of relevant signaling pathways, the adaptive stress response is emerging as a new spotlight of drug resistance in cancer cells. Stress granules (SGs) are one of the most important features of the adaptive stress response, and there is increasing evidence that SGs promote drug resistance in cancer cells. In the present study, we compared two types of ovarian cancer cells, A2780 and SKOV3, using the dual PI3K/mTOR inhibitor, PKI-402. We found that SGs were formed and SGs could intercept the signaling factor ATF5 and regulate the mitochondrial unfolded protein response (UPR mt ) in A2780 cells. Therefore, exploring the network formed between SGs and membrane-bound organelles, such as mitochondria, which may provide a new insight into the mechanisms of antitumor drug functions.

Efficient detection of related markers is significant for the early screening of COVID-19. Near infrared (NIR) light excited up-conversion fluorescence probes are ideal for biosensing but limited by the low luminescence effi-ciency. In this work, a novel highly stable opal photonic crystal (OPC) structure was designed to provide an OPC effect for up-conversion fluorescence enhancement, and sensitive Novel Coronavirus IgG up-conversion FRET-based sensor was further constructed. For the problems of water stability and mechanical stability of polymer OPC which cannot be solved for a long time, polymer spray combined with a flipped OPC film strategy is pre-sented. Fragmented size OPC film was firmly fixed by polymer modification layer, which gave large size OPC film great water stability, mechanical stability and bending performance without affecting the fluorescence enhancement property. On this basis, the up-conversion emission intensity was enhanced significantly, and fluorescence resonant energy transfer (FRET) based Novel Coronavirus IgG antibody sensor was constructed. Monolayer up-conversion nanoparticles (UCNPs) on the surface of the polydopamine (PDA)/OPC film can make the fluorescent signal more sensitive, and effectively reduce the detection limit. The test device integrating NIR excitation and mobile phone realized the visual fast detection, showing remarkable sensing performance for COVID-19 antibodies with the limit of detection (LOD) of 0.1 ng mL-1. This detection platform will provide a more effective tool for early detection of the novel coronavirus.

Mitochondria are the only organelles regulated by two genomes. The coordinated translation of nuclear DNA (nDNA) and mitochondrial DNA (mtDNA), which together co-encode the subunits of the oxidative phosphorylation (OXPHOS) complex, is critical for determining the metabolic plasticity of tumor cells. RNA-binding protein (RBP) is a post-transcriptional regulatory factor that plays a pivotal role in determining the fate of mRNA. RBP rapidly and effectively reshapes the mitochondrial proteome in response to intracellular and extracellular stressors, mediating the cytoplasmic and mitochondrial translation balance to adjust mitochondrial respiratory capacity and provide energy for tumor cells to adapt to different environmental pressures and growth needs. This review highlights the ability of RBPs to use liquid–liquid phase separation (LLPS) as a platform for translation regulation, integrating nuclear–mitochondrial positive and retrograde signals to coordinate cross-department translation, reshape mitochondrial energy metabolism, and promote the development and survival of tumor cells.

Abstract Background：The liver is the main organ that coordinates metabolic flexibility and participates in nutrient metabolism; and liver injury caused by alcoholic hepatitis, viral hepatitis or fatty liver has become increasingly more prevalent. Thus, it is urgent to explore the specific mechanisms that underlie the pathology of liver injury. Current research focuses on oxidative stress and inflammation as the major causes of acute liver injury, and interleukin-33 (IL-33) is thought to have an integral role, though its contributing mechanisms remain unclear. Methods：In the present study, we evaluated the coordinated roles of stress and inflammation in CCl4-induced acute liver injury in IL-33-overexpressing mice. Results：Our results demonstrate for the first time that concurrent treatment with the mitochondrial respiratory chain complex 1 inhibitor metformin enhances mitochondrial biosynthesis and alleviates acute liver injury in IL-33-overexpressing mice with CCl4-induced injury.These results were supported by the ability of metformin to reverse changes in liver tissue pathology, AST/ALT levels, inflammatory and stress related signaling pathways, oxidative response markers, and mitochondrial respiratory chain complex subunits. Conclusion： These results provide a mechanistic basis for the activity of metformin in alleviating acute liver injury. Metformin alleviates CCl4-Induced acute liver injury in IL-33-Overexpressing mice by targeting mitochondrial pathway-dependent oxidative stress and inflammation. When CCl4 was used as a strong stressor of liver injury, IL-33+ mice were more adaptive to the stress response, resulting in better effectiveness of metformin in ameliorating liver injury.

肿瘤细胞暴露于基因组不稳定、氧化应激、营养缺乏和蛋白稳态失衡等复杂应激环境下,通过激活整合应激反应(ISR)来抵抗各种形式应激产生的损伤作用.如果ISR无法修复损伤,将通过启动死亡程序清除受损细胞.ISR介导的这种存活和死亡之间的平衡对于肿瘤的发生至关重要.目前研究认为ISR主要包括内质网未折叠蛋白反应(UPRER )和线粒体未折叠蛋白反应(UPRmt ),已经明确 UPRER和UPRmt中多个效应分子在肿瘤发生过程中的作用.近来研究表明,ISR 通过其枢纽分子 eIF2α整合UPRER和UPRmt的应激信号,eIF2α表达和磷酸化水平决定了 ISR 是促进肿瘤细胞存活还是死亡.因此,探讨ISR在肿瘤发生中的作用机制有望为肿瘤的治疗提供新靶点.

目的:按照教育部和学校"停课不停教、停课不停学"的工作部署,为保障学生在疫情期间的学习病理生理学进行线上教学.方法:线上教学应用网络平台与自建课程相结合的方式,在课程设计上,增加小视频,科技前沿、新冠疫情、思政等元素,在实施过程注重知识传授及价值的引领,在教学完成后对教学效果进行及时检验,最后,通过教学反馈进行教学效果反思.结果:教学改革将现代化信息技术与教学相结合,激发学生的学习兴趣,提高了学生的学习深度,促进了教师教学能力的提升.结论:线上教学是教学改革的一个新尝试,为今后的线上线下混合教学奠定了基础.

Skeletal muscles require muscle satellite cell (MuSC) differentiation to facilitate the replenishment and repair of muscle fibers. A key step in this process is called myogenic differentiation. The differentiation ability of MuSCs decreases with age and can result in sarcopenia. Although mitochondria have been reported to be involved in myogenic differentiation by promoting a bioenergetic remodeling, little is known about the interplay of mitochondrial proteostasis and myogenic differentiation. High-temperature-requirement protein A2 (HtrA2/Omi) is a protease that regulates proteostasis in the mitochondrial intermembrane space (IMS). Mice deficient in HtrA2 protease activity show a distinct phenotype of sarcopenia. To investigate the role of IMS proteostasis during myogenic differentiation, we treated C2C12 myoblasts with UCF101, a specific inhibitor of HtrA2 during differentiation process. A key step in this process is called myogenic differentiation. The differentiation ability of MuSCs decreases with age and can result in sarcopenia. Further, CHOP, p-eIF2α, and other mitochondrial unfolded protein response (UPRmt)-related proteins are upregulated. Therefore, we suggest that imbalance of mitochondrial IMS proteostasis acts via a retrograde signaling pathway to inhibit myogenic differentiation via the UPRmt pathway. These novel mechanistic insights may have implications for the development of new strategies for the treatment of sarcopenia.

Chemotherapeutic drug-induced p53-dependent crosstalk among tumor cells affects the sensitivity of tumor cells to chemotherapeutic drugs, contributing to chemoresistance. Therefore, pharmacological targeting of p53 may contribute to overcoming drug resistance. The localization of p53 is closely related to its function. Thus, we assessed the effect of p62 on the coordination of p53 mitochondrial localization under chemotherapeutic drug treatment in ovarian cancer cells. We found that the combined use of the proteasome inhibitor epoxomicin and cisplatin led to the accumulation of p53 and sequestosome1(p62) in the mitochondria, downregulated mitochondrial DNA (mtDNA) transcription, inhibited mitochondrial functions, and ultimately promoted apoptosis by enhancing cisplatin sensitivity in ovarian cancer cells. Moreover, the ubiquitin-associated (UBA) domain of p62 was involved in regulating the mitochondrial localization of p53. Our findings suggest that the interaction between p62 and p53 may be a mechanism that determines the fate of tumor cells. In conclusion, p62 coordinated the mitochondrial localization of p53 through its UBA domain, inhibited mtDNA transcription, downregulated mitochondrial function, and promoted ovarian cancer cell death. Our study demonstrates the important role of p53 localization in tumor cell survival and apoptosis, and provides new insights into understanding the anti-tumor mechanism of targeting the ubiquitin–proteasome system in tumor cells.

Interactions between the mitochondrial inner and outer membranes and between mitochondria and other organelles closely correlates with the sensitivity of ovarian cancer to cisplatin and other chemotherapeutic drugs. However, the underlying mechanism remains unclear. Recently, the mitochondrial protease OMA1, which regulates internal and external signals in mitochondria by cleaving mitochondrial proteins, was shown to be related to tumor progression. Therefore, we evaluated the effect of OMA1 on the response to chemotherapeutics in ovarian cancer cells and the mouse subcutaneous tumor model. We found that OMA1 activation increased ovarian cancer sensitivity to cisplatin in vivo and in vitro. Mechanistically, in ovarian cancer, OMA1 cleaved optic atrophy 1 (OPA1), leading to mitochondrial inner membrane cristae remodeling. Simultaneously, OMA1 induced DELE1 cleavage and its cytoplasmic interaction with EIF2AK1. We also demonstrated that EIF2AK1 cooperated with the ER stress sensor EIF2AK3 to amplify the EIF2S1/ATF4 signal, resulting in the rupture of the mitochondrial outer membrane. Knockdown of OMA1 attenuated these activities and reversed apoptosis. Additionally, we found that OMA1 protease activity was regulated by the prohibitin 2 (PHB2)/stomatin-like protein 2 (STOML2) complex. Collectively, OMA1 coordinates the mitochondrial inner and outer membranes to induce ovarian cancer cell death. Thus, activating OMA1 may be a novel treatment strategy for ovarian cancer.

The changes of mitochondrial function are closely related to diabetes and its complications. Here we describe the effects of mitochondrial-derived peptides (MDPs), short peptides formed by transcription and translation of the open reading frame site in human mitochondrial DNA (mtDNA), on diabetes and its complications. We mainly focus on MDPs that have been discovered so far, such as Humanin (HN), mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) and Small humanin-like peptides (SHLP 1-6), and elucidated the role of MDPs in diabetes and its major complications stroke and myocardial infarction by improving insulin resistance, inhibiting inflammatory response and anti-apoptosis. It provides more possibilities for the clinical application of mitochondrial derived peptides.

Purpose Magnetic iron oxide nanoparticle (MNP) drug delivery system is a novel promising therapeutic option for cancer treatment. Material issues such as fabrication and functionalized modification have been investigated; however, pharmacologic mechanisms of bare MNPs inside cancer cells remain obscure. This study aimed to explore a systems pharmacology approach to understand the reaction of the whole cell to MNPs and suggest drug selection in MNP delivery systems to exert synergetic or additive anti-cancer effects. Methods HeLa and SiHa cell lines were used to estimate the properties of bare MNPs in cervical cancer through 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) and enzyme activity assays and cellular fluorescence imaging. A systems pharmacology approach was utilized by combining bioinformatics data mining with clinical data analysis and without a predefined hypothesis. Key genes of the MNP onco-pharmacologic mechanism in cervical cancer were identified and further validated through transcriptome analysis with quantitative reverse transcription PCR (qRT-PCR). Results Low cytotoxic activity and cell internalization of MNP in HeLa and SiHa cells were observed. Lysosomal function was found to be impaired after MNP treatment. Protein tyrosine kinase 2 beta (PTK2B), liprin-alpha-4 (PPFIA4), mothers against decapentaplegic homolog 7 (SMAD7), and interleukin (IL) 1B were identified as key genes relevant for MNP pharmacology, clinical features, somatic mutation, and immune infiltration. The four key genes also exhibited significant correlations with the lysosome gene set. The qRT-PCR results showed significant alterations in the expression of the four key genes after MNP treatment in HeLa and SiHa cells. Conclusion Our research suggests that treatment of bare MNPs in HeLa and SiHa cells induced significant expression changes in PTK2B, PPFIA4, SMAD7, and IL1B, which play crucial roles in cervical cancer development and progression. Interactions of the key genes with specific anti-cancer drugs must be considered in the rational design of MNP drug delivery systems.

[This corrects the article DOI: 10.7150/ijbs.46822.].