Acute mitochondrial damage and the energy crisis following axonal injury highlight mitochondrial transport as an important target for axonal regeneration. Syntaphilin (Snph), known for its potent mitochondrial anchoring action, has emerged as a significant inhibitor of both mitochondrial transport and axonal regeneration. Therefore, investigating the molecular mechanisms that influence the expression levels of the snph gene can provide a viable strategy to regulate mitochondrial trafficking and enhance axonal regeneration. Here, we reveal the inhibitory effect of microRNA-146b (miR-146b) on the expression of the homologous zebrafish gene syntaphilin b (snphb). Through CRISPR/Cas9 and single-cell electroporation, we elucidated the positive regulatory effect of the miR-146b-snphb axis on Mauthner cell (M-cell) axon regeneration at the global and single-cell levels. Through escape response tests, we show that miR-146b-snphb signaling positively regulates functional recovery after M-cell axon injury. In addition, continuous dynamic imaging in vivo showed that reprogramming miR-146b significantly promotes axonal mitochondrial trafficking in the pre-injury and early stages of regeneration. Our study reveals an intrinsic axonal regeneration regulatory axis that promotes axonal regeneration by reprogramming mitochondrial transport and anchoring. This regulation involves noncoding RNA, and mitochondria-associated genes may provide a potential opportunity for the repair of central nervous system injury.
Animals ; Zebrafish ; MicroRNAs/genetics* ; Nerve Regeneration/physiology* ; Mitochondria/metabolism* ; Zebrafish Proteins/genetics* ; Axons/metabolism* ; Signal Transduction/physiology* ; Axonal Transport/physiology* ; Nerve Tissue Proteins/genetics*

Periodontitis is a common oral disease characterized by progressive alveolar bone resorption and inflammation of the periodontal tissues. Dimethyl fumarate (DMF) has been used in the treatment of various immune-inflammatory diseases due to its excellent anti-inflammatory and antioxidant functions. Here, we investigated for the first time the therapeutic effect of DMF on periodontitis. In vivo studies showed that DMF significantly inhibited periodontal destruction, enhanced mitophagy, and decreased the M1/M2 macrophage ratio. In vitro studies showed that DMF inhibited macrophage polarization toward M1 macrophages and promoted polarization toward M2 macrophages, with improved mitochondrial function, inhibited oxidative stress, and increased mitophagy in RAW 264.7 cells. Furthermore, DMF increased intracellular mitochondrial Tu translation elongation factor (TUFM) levels to maintain mitochondrial homeostasis, promoted mitophagy, and modulated macrophage polarization, whereas TUFM knockdown decreased the protective effect of DMF. Finally, mechanistic studies showed that DMF increased intracellular TUFM levels by protecting TUFM from degradation via the ubiquitin-proteasomal degradation pathway. Our results demonstrate for the first time that DMF protects mitochondrial function and inhibits oxidative stress through TUFM-mediated mitophagy in macrophages, resulting in a shift in the balance of macrophage polarization, thereby attenuating periodontitis. Importantly, this study provides new insights into the prevention of periodontitis.
Dimethyl Fumarate/pharmacology* ; Mitophagy/drug effects* ; Animals ; Mice ; Macrophages/metabolism* ; Periodontitis/prevention & control* ; RAW 264.7 Cells ; Oxidative Stress/drug effects* ; Peptide Elongation Factor Tu/metabolism* ; Mice, Inbred C57BL ; Male ; Mitochondria/drug effects*

Mitochondria are the convergence point of multiple pathways that trigger programmed cell death (PCD). Mitochondrial-associated PCD (mtPCD) is involved in the pathogenesis of several diseases. However, the role of mtPCD in the prognostic prediction of cancers including non-small-cell lung cancer (NSCLC) remains to be investigated. Here, 12 mtPCD patterns were analyzed in transcriptomics, genomics, and clinical data collected from 4 datasets containing 977 patients. A risk-score assessment system containing 18 genes was established. We found that NSCLC patients with a high-risk score had a poorer prognosis. A nomogram was constructed by incorporating the risk score with clinical features. The risk score was further associated with clinicopathological information, tumor-mutation frequency, and immunotherapy responses. NSCLC patients with a high risk score had more Treg cells infiltration. However, these patients had higher tumor-mutation burden scores and may be more sensitive to immunotherapy. Moreover, receptor-interacting serine/threonine protein kinase 2 (RIPK2) was selected from mtPCD gene model for validation. We found that RIPK2 exhibited oncogenic function, and its expression level was inversely associated with the overall survival of NSCLC. Taken together, our results indicated the accuracy and practicability of the mtPCD gene model and RIPK2 in predicting the prognosis of NSCLC.
Humans ; Carcinoma, Non-Small-Cell Lung/pathology* ; Lung Neoplasms/pathology* ; Prognosis ; Male ; Female ; Nomograms ; Middle Aged ; Mitochondria/metabolism* ; Apoptosis/genetics* ; Mutation ; Biomarkers, Tumor/genetics* ; Aged

Diabetic cardiomyopathy (DCM) is a medical condition characterized by cardiac remodeling and dysfunction in individuals with diabetes mellitus. Sarcoplasmic reticulum (SR) and mitochondrial Ca²⁺ overload in cardiomyocytes have been recognized as biological hallmarks in DCM; however, the specific factors underlying these abnormalities remain largely unknown. In this study, we aimed to investigate the role of a cardiac-specific long noncoding RNA, D830005E20Rik (Trdn-as), in DCM. Our results revealed the remarkably upregulation of Trdn-as in the hearts of the DCM mice and cardiomyocytes treated with high glucose (HG). Knocking down Trdn-as in cardiac tissues significantly improved cardiac dysfunction and remodeling in the DCM mice. Conversely, Trdn-as overexpression resulted in cardiac damage resembling that observed in the DCM mice. At the cellular level, Trdn-as induced Ca²⁺ overload in the SR and mitochondria, leading to mitochondrial dysfunction. RNA-seq and bioinformatics analyses identified calsequestrin 2 (Casq2), a primary calcium-binding protein in the junctional SR, as a potential target of Trdn-as. Further investigations revealed that Trdn-as facilitated the recruitment of METTL14 to the Casq2 mRNA, thereby enhancing the m⁶A modification of Casq2. This modification increased the stability of Casq2 mRNA and subsequently led to increased protein expression. When Casq2 was knocked down, the promoting effects of Trdn-as on Ca²⁺ overload and mitochondrial damage were mitigated. These findings provide valuable insights into the pathogenesis of DCM and suggest Trdn-as as a potential therapeutic target for this condition.
Animals ; Diabetic Cardiomyopathies/pathology* ; RNA, Long Noncoding/genetics* ; Myocytes, Cardiac/metabolism* ; Mice ; Calsequestrin/genetics* ; Calcium/metabolism* ; Male ; Sarcoplasmic Reticulum/metabolism* ; Methyltransferases/metabolism* ; Mice, Inbred C57BL ; Mitochondria, Heart/metabolism* ; Disease Models, Animal ; Mitochondria/metabolism*

Lactic acid (LA) accumulation in tumor microenvironments (TME) has been implicated in immune suppression and tumor progress. Diverse roles of LA have been elucidated, including microenvironmental pH regulation, signal transduction, post-translational modification, and metabolic remodeling. This review summarizes LA functions within TME, focusing on the effects on tumor cells, immune cells, and stromal cells. Reducing LA levels is a potential strategy to attack cancer, which inevitably affects the physiological functions of normal tissues. Alternatively, transporting LA into the mitochondria as an energy source for immune cells is intriguing. We underscore the significance of LA in both tumor biology and immunology, proposing the burning of LA as a potential therapeutic approach to enhance antitumor immune responses.
Humans ; Tumor Microenvironment/immunology* ; Neoplasms/therapy* ; Lactic Acid/immunology* ; Mitochondria/metabolism* ; Animals ; Signal Transduction

Patients with severe pneumonia caused by novel coronavirus infection are often complicated with acute respiratory distress syndrome (ARDS), which has a high mortality. ARDS is characterized by diffuse alveolar damage, pulmonary edema, and hypoxemia. Mitochondria are prone to morphological and functional abnormalities under hypoxia and viral infection, which can lead to cell apoptosis and damage, severely impacting the disease progression. Mitochondria maintain homeostasis through fission and fusion. In ARDS, hypoxia leads to the phosphorylation of dynamin-related protein 1 (Drp1), triggering excessive mitochondrial fission and damaging the alveolar epithelial barrier. Animal experiments have shown that inhibiting this process can alleviate lung injury, providing a potential direction for treatment. The pathology of novel coronavirus infection-related ARDS is similar to that of typical ARDS but more severe. Viral infection and hypoxia disrupt the mitochondrial balance, causing fission and autophagy abnormalities, promoting oxidative stress and mitochondrial DNA (mtDNA) release, activating inflammasomes, inducing the expression of hypoxia-inducible factor-1α (HIF-1α), exacerbating viral infection, inflammation, and coagulation reactions, and resulting in multiple organ damage. Mechanical ventilation and glucocorticoids are commonly used in the treatment of novel coronavirus infection-related ARDS. Mechanical ventilation is likely to cause lung and diaphragm injuries and changes in mitochondrial dynamics, while the lung protective ventilation strategy can reduce the adverse effects. Glucocorticoids can regulate mitochondrial function and immune response and improve the patient's condition through multiple pathways. The mitochondrial dynamics imbalance in novel coronavirus infection-related ARDS is caused by hypoxia and viral proteins, leading to lung and multiple organ injuries. To clarify the pathophysiological mechanism of mitochondrial dynamics imbalance in novel coronavirus infection-related ARDS and explore effective strategies for regulating mitochondrial dynamics balance to treat this disease, so as to provide new treatment targets and methods for patients with novel coronavirus infection-related ARDS. The existing treatments have limitations. Future research needs to deeply study the mechanism of mitochondrial dysfunction, develop new therapies and regulatory strategies, and improve the treatment effect.
Humans ; Respiratory Distress Syndrome/etiology* ; COVID-19 ; Mitochondrial Dynamics ; Mitochondria/metabolism* ; DNA, Mitochondrial ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism* ; Dynamins ; SARS-CoV-2

Activating transcription factor 5 (ATF5) is a member of the activating transcription factor/cyclic adenosine monophosphate response element binding protein (ATF/CREB) family. As a stress-induced transcription factor, ATF5 plays a crucial role in cellular inflammatory stress responses. Under cellular inflammatory stress conditions, ATF5 maintains cell homeostasis and survival by regulating key genes in the mitochondrial unfolded protein response (UPR^mt) and endoplasmic reticulum stress (ERS). As a key regulator in UPR^mt, ATF5 senses mitochondrial stress and translocate to the nucleus to activate the transcription of UPR^mt-related genes, thereby promoting mitochondrial function recovery. Meanwhile, in ERS, ATF5 maintains endoplasmic reticulum homeostasis by regulating the expression of genes related to protein folding, degradation, and apoptosis, determining cell survival or death. ATF5 plays a vital role in various cellular inflammatory stress responses. In infectious inflammation, ATF5 plays an important role in alleviating neuroinflammation and maintaining intestinal barrier function by regulating UPR^mt. In inflammation related to degenerative diseases, ATF5 improves intervertebral disc degeneration and delays the progression of osteoarthritis by regulating UPR^mt. In metabolic inflammation such as diabetes and obesity, ATF5 regulates UPR^mt and ERS to maintain the function of pancreatic β-cells, controlling their survival or inducing apoptosis, thus influencing the progression of diabetes. ATF5 protects mitochondria in the kidneys, adipose tissue, and pancreas, slows the progression of diabetic nephropathy, and improves insulin sensitivity. Furthermore, in immune-related inflammation, ATF5 alleviates glomerulonephritis and promotes tissue repair by enhancing immune tolerance in dendritic cells. In summary, ATF5, as a key regulator in cellular inflammatory stress responses, maintains cell homeostasis through regulating UPR^mt and ERS and determines cell fate. Its critical regulatory role in cellular inflammatory stress responses makes ATF5 a potential clinical therapeutic target. This article summarizes the structural features and translational regulatory mechanisms of ATF5, focusing on its role in cellular inflammatory stress responses, particularly its regulatory mechanisms in UPR^mt and ERS, aiming to provide a theoretical basis for understanding ATF5's role in cell and organ protection and to offer new insights into the treatment of related inflammatory diseases.
Humans ; Endoplasmic Reticulum Stress ; Inflammation/metabolism* ; Activating Transcription Factors/metabolism* ; Unfolded Protein Response ; Mitochondria/metabolism* ; Apoptosis ; Animals

Sepsis-associated encephalopathy (SAE) is one of the complications of sepsis, causes cognitive dysfunction ranging from mild attention deficits to progression into coma, which severely impairs patients' ability to live and mental health, and increases the long-term disability and mortality rates. Although the clinical attention to SAE has been increasing in recent years, effective interventions to improve cognitive dysfunction in sepsis survivors are still in the preclinical stage. The pathogenesis of SAE is numerous and complex, and mitochondrial dysfunction, as one of the key pathogenic mechanisms, plays a role in the cognitive development process through oxidative stress imbalance, energy metabolism disorders, and activation of apoptosis signaling pathway. The present review systematically integrates the recent studies on mitochondrial dysfunction in the development of cognitive disorders. This review systematically integrates the cutting-edge research results in recent years, discusses the mitochondrial structural disruption, mitochondrial kinetic abnormalities, respiratory chain dysfunction, and comprehensively comprehends the research progress of mitochondria-targeted antioxidant, mitochondrial autophagy activator, mitochondrial biosynthesis modifier and other novel intervention strategies in improving cognitive function of SAE patients, with the aim of providing theoretical basis for the breakthrough of the current status of clinical treatment of SAE and the targeting of mitochondria for treatment. The aim is to provide theoretical basis for breaking through the status of SAE clinical treatment and targeting mitochondrial therapy.
Humans ; Sepsis-Associated Encephalopathy/metabolism* ; Mitochondria/metabolism* ; Sepsis/complications* ; Oxidative Stress ; Cognitive Dysfunction ; Autophagy

Sepsis-acquired weakness (SAW) is a common complication in critically ill patients, yet significant gaps remain in both mechanistic understanding and therapeutic interventions for this condition. SAW not only prolongs the duration of mechanical ventilation and hospitalization but is also closely associated with increased mortality. Even if these SAW patients survive, they often experience long-term physical dysfunction after hospital discharge, leading to diminished quality of life. Emerging evidence suggests that sustained mitochondrial dysfunction may constitute a pivotal pathophysiological basis for the development and progression of SAW, primarily encompassing five key aspects: dysregulated mitochondrial quality control (MtQC), impaired oxidative phosphorylation (OXPHOS), exacerbated oxidative stress, disrupted Ca²⁺; homeostasis, and their mediation of diverse myofiber injuries. This article systematically elucidates the central role of mitochondrial dysfunction in the pathogenesis of SAW. Furthermore, we explore potential therapeutic strategies targeting mitochondrial function, including mitigating mitochondrial oxidative stress, optimizing nutritional support, and supplementing with muscle-derived mesenchymal stem cells. These insights provide a critical theoretical framework for understanding SAW mechanisms and developing clinical interventions, with particular emphasis on the translational value of mitochondrial-targeted therapies in improving outcomes for septic patients.
Humans ; Sepsis/metabolism* ; Mitochondria/metabolism* ; Muscle Weakness/etiology* ; Oxidative Stress ; Oxidative Phosphorylation

The activation of the sirtuin1 (SIRT1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway has been shown to mitigate oxidative stress-induced apoptosis and mitochondrial damage by reducing reactive oxygen species (ROS) levels. Clinical trials have demonstrated that Zhongfeng Xingnao Liquid (ZFXN) ameliorates post-stroke cognitive impairment (PSCI). However, the underlying mechanism, particularly whether it involves protecting mitochondria and inhibiting apoptosis through the SIRT1/Nrf2/HO-1 pathway, remains unclear. This study employed an oxygen-glucose deprivation (OGD) cell model using SH-SY5Y cells and induced PSCI in rats through modified bilateral carotid artery ligation (2VO). The effects of ZFXN on learning and memory, neuroprotective activity, mitochondrial function, oxidative stress, and the SIRT1/Nrf2/HO-1 pathway were evaluated both in vivo and in vitro. Results indicated that ZFXN significantly increased the B-cell lymphoma 2 (Bcl2)/Bcl2-associated X (Bax) ratio, reduced terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling (TUNEL)⁺ cells, and markedly improved cognition, synaptic plasticity, and neuronal function in the hippocampus and cortex. Furthermore, ZFXN exhibited potent antioxidant activity, evidenced by decreased ROS and malondialdehyde (MDA) content and increased superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) levels. ZFXN also demonstrated considerable enhancement of mitochondrial membrane potential (MMP), Tom20 fluorescence intensity, adenosine triphosphate (ATP) and energy charge (EC) levels, and mitochondrial complex I and III activity, thereby inhibiting mitochondrial damage. Additionally, ZFXN significantly increased SIRT1 activity and elevated SIRT1, nuclear Nrf2, and HO-1 levels. Notably, these effects were substantially counteracted when SIRT1 was suppressed by the inhibitor EX-527 in vitro. In conclusion, ZFXN alleviates PSCI by activating the SIRT1/Nrf2/HO-1 pathway and preventing mitochondrial damage.
Sirtuin 1/genetics* ; Animals ; NF-E2-Related Factor 2/genetics* ; Cognitive Dysfunction/genetics* ; Male ; Rats, Sprague-Dawley ; Rats ; Humans ; Signal Transduction/drug effects* ; Drugs, Chinese Herbal/administration & dosage* ; Heme Oxygenase-1/genetics* ; Stroke/complications* ; Oxidative Stress/drug effects* ; Apoptosis/drug effects* ; Mitochondria/metabolism* ; Reactive Oxygen Species/metabolism* ; Neuroprotective Agents