This study investigates the role of Gelatin-Catalase (Gel@CAT)-L hydrogel in mediating reactive oxygen species (ROS) production and maintaining mitochondrial homeostasis through SIRT3-mediated unfolded protein response (UPRmt), while exploring its involvement in the molecular mechanism of osteoarthritis (OA).

Self-assembled Gel@CAT-L hydrogels were fabricated and characterized using transmission electron microscopy, mechanical testing, external release property evaluation, and oxygen production measurement. Biocompatibility was assessed via live/dead cell staining and CCK8 assays. An OA mouse model was established using destabilization of the medial meniscus (DMM) surgery. X-ray and micro-CT imaging were employed to evaluate the structural integrity of the mouse knee joints, while histological staining was used to assess cartilage degeneration. Immunohistochemistry was performed to analyze the expression of proteins including Col2a1, Aggrecan, MMP13, ADAMTS5, SIRT3, PINK1, and Parkin. Multi-omics analyses-encompassing high-throughput sequencing, proteomics, and metabolomics-were conducted to identify key genes and metabolic pathways targeted by Gel@CAT-L hydrogel intervention in OA. Immunofluorescence techniques were utilized to measure ROS levels, mitochondrial membrane potential, and the expression of SIRT3, PINK1, Parkin, LYSO, LC3B, Col2a1, and MMP13 in primary mouse chondrocytes and mouse knee joints. Flow cytometry was applied to quantify ROS-positive cells. RT-qPCR analysis was conducted to determine mRNA levels of Aggrecan, Col2a1, ADAMTS5, MMP13, SIRT3, mtDNA, HSP60, LONP1, CLPP, and Atf5 in primary mouse chondrocytes, mouse knee joints, and human knee joints. Western blotting was performed to measure protein expression levels of SIRT3, HSP60, LONP1, CLPP, and Atf5 in both primary mouse chondrocytes and mouse knee joints. Additionally, 20 samples each from the control (CON) and OA groups were collected for analysis. Hematoxylin and eosin staining was used to evaluate cartilage degeneration in human knee joints. The Mankin histological scoring system quantified the degree of cartilage degradation, while immunofluorescence analyzed SIRT3 protein expression in human knee joints.

In vitro experiments demonstrated that self-assembled Gel@CAT-L hydrogels exhibited excellent biodegradability and oxygen-releasing capabilities, providing a stable three-dimensional environment conducive to cell viability and proliferation while reducing ROS levels. Multi-omics analysis identified SIRT3 as a key regulatory gene in mitigating OA and revealed its central role in the UPRmt pathway. Furthermore, Gel@CAT-L was confirmed to regulate mitochondrial homeostasis. Both in vitro experiments and in vivo mouse model studies confirmed that Gel@CAT-L significantly reduced ROS levels and regulated mitochondrial autophagy by activating the SIRT3-mediated UPRmt pathway, thereby improving the pathological state of OA. Clinical trials indicated downregulation of SIRT3 and UPRmt-related proteins in OA patients.

Gel@CAT-L hydrogel activates SIRT3-mediated UPRmt to regulate ROS and mitochondrial homeostasis, providing potential therapeutic benefits for OA.

The mitochondrial unfolded protein response (UPRmt) is an intracellular retrograde signaling process that facilitates the restoration of mitochondrial homeostasis. Mitochondria are essential for neuronal signaling, and their dysfunction has been implicated as a significant mechanism in the development of chronic pain. Nevertheless, little is known about the exact function of UPRmt in bone cancer pain (BCP). This research intended to explore the connection between UPRmt and the progression of BCP. In BCP group, the ultrastructure of spinal cord mitochondria was disrupted, accompanied by a decline in ATP levels and a decrease in Mitochondrial membrane potential (MMP). Concurrently, mRNA and protein levels of UPRmt marker proteins (Atf5, Hsp60, LonP1, and ClpP) were upregulated, with the expression of Atf5, a key transcription factor of UPRmt, notably enhanced in spinal dorsal horn neurons. Nicotinamide riboside (NR)-mediated pharmacological augmentation of the UPRmt significantly alleviated BCP-induced nociceptive hypersensitivity, as demonstrated by elevated mechanical withdrawal thresholds and diminished spontaneous flinching behavior. Concomitant mitochondrial functional recovery was evidenced by restoration of MMP and normalization of ATP level. Notably, genetic knockdown of activating transcription factor 5 (Atf5) abolished both NR-induced UPRmt activation and the consequent protection against rotenone-mediated mitochondrial dysfunction. These findings establish UPRmt potentiation as an effective strategy for ameliorating mitochondrial dysfunction and attenuating BCP-associated nociception, proposing this pathway as a novel therapeutic target for clinical pain management.

The mitochondrial unfolded protein response (UPRmt), an evolutionarily conserved proteostasis pathway, plays a critical role in the pathogenesis of Alzheimer's disease (AD), characterized by amyloid-β peptide (Aβ) aggregation. Although the transcription factor DVE-1 regulates UPRmt activation in C. elegans and has been implicated in Aβ pathology, its regulatory mechanisms under AD-like conditions remain unclear. Here, using the classical C. elegans muscle-specific AD model (CL2006 strain), we observed UPRmt induction in young adults despite paradoxical depletion of DVE-1 protein concurrent with elevated dve-1 transcript levels. Through integrated genetic and biochemical analyses, we identified SIAH-1, a conserved E3 ubiquitin ligase that partners with the E2 enzyme UBC-25 to interact with DVE-1 and mediate its K48-linked polyubiquitination, as targeting DVE-1 for proteasomal degradation. Disruption of SIAH-1 E3 ubiquitin ligase function or overexpression of DVE-1 significantly reduced Aβ toxicity in both the muscle-expressed Aβ (CL2006) and neuronal Aβ models (gnaIs2). These interventions concurrently suppressed Aβ aggregation in the heat shock-inducible Aβ aggregation model (xchIs15). Mechanistically, this protective effect was associated with restored mitochondrial homeostasis, as evidenced by MitoTracker Red staining and TOMM-20::mCherry fluorescence imaging in muscle-expressed Aβ animals. These assays demonstrated that Aβ accumulation compromises mitochondrial integrity, a phenotype markedly rescued in siah-1 deletion mutants and DVE-1-overexpressing strains. Collectively, these findings establish the SIAH-1/DVE-1 axis as a conserved proteostasis regulator and highlight ubiquitin-dependent mitochondrial quality control as a potential therapeutic target for AD and related proteopathies.

Chondrocyte senescence is a critical pathological hallmark of osteoarthritis (OA). Aberrant mechanical stress is considered a pivotal determinant in chondrocyte aging; however, the precise underlying mechanism remains elusive. Our findings demonstrate that SPI1 plays a significant role in counteracting chondrocyte senescence and inhibiting OA progression. SPI1 binds to the PERK promoter, thereby promoting its transcriptional activity. Importantly, PERK, rather than GCN2, facilitates eIF2α phosphorylation, activating the mitochondrial unfolded protein response (UPRmt) and impeding chondrocyte senescence. Deficiency of SPI1 in mechanical overload-induced mice leads to diminished UPRmt activation and accelerated OA progression. Intra-articular injection of adenovirus vectors overexpressing SPI1 and PERK effectively mitigates cartilage degeneration. In summary, our study elucidates the crucial regulatory role of SPI1 in the pathogenesis of chondrocyte senescence by activating UPRmt signaling through PERK, which may present a novel therapeutic target for treating OA. SPI1 alleviates the progression of OA by inhibiting mechanical stress-induced chondrocyte senescence through mitochondrial UPR signaling.

To explore the underlying mechanism behind the fine particulate matter's (PM2.5)-mediated regulation of reproductive function in male rats, and to determine the role of vitamins in this process.

In all, 32 male SD rats were randomized to a control cohort (normal saline), a Vit cohort (vitamin C at 100 mg/kg +  vitamin E at 50 mg/kg), a PM2.5 cohort (PM2.5 10 mg/kg), and a PM2.5 + Vit cohort (PM2.5 exposure +  vitamin C at 100 mg/kg +  vitamin E at 50 mg/kg), with eight rats in each cohort. After four weeks of exposure, mating experiments were carried out. Thereafter, rats were euthanized, and the testis and epididymis tissues were excised for hematoxylin-eosin (HE) staining and sperm quality analysis. Apoptosis of testis tissues was quantified via a terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Moreover, the testicular oxidative stress (OS)-, apoptosis- and mitochondrial unfolded protein response (UPRmt)-related essential protein expressions were measured via western blotting (WB).

After PM2.5 exposure, the sperm count and motility decreased, while sperm abnormality and the apoptosis index increased. HE staining showed that the number of spermatogenic cells decreased. WB showed that the PM2.5 group had decreased expressions of superoxide dismutase (SOD), nuclear factor E2-related factor 2 (Nrf2), and B-cell lymphoma-2 (Bcl-2) (p <  0.05), increased expressions of malondialdehyde (MDA), Bcl-2 associated X protein (Bax), and Caspase3 (p <  0.05), and downregulated expressions of C/EBP homologous protein (CHOP), heat shock protein 60 (HSP60), and activating transcription factor 5 (ATF5) (p <  0.05). These were all reversed by vitamin intervention.

PM2.5 from automobile exhaust disrupts male reproductive function. A combination of vitamins may protect reproductive function via the reactive oxygen species (ROS)-UPRmt signaling pathway.

Mitochondria are often referred to as the energy centers of the cell and are recognized as key players in signal transduction, sensing, and responding to internal and external stimuli. Under stress conditions, the mitochondrial unfolded protein response (UPRmt), a conserved mitochondrial quality control mechanism, is activated to maintain mitochondrial and cellular homeostasis. As a physiological stimulus, exercise-induced mitochondrial perturbations trigger UPRmt, coordinating mitochondria-to-nucleus communication and initiating a transcriptional program to restore mitochondrial function. The aim of this study was to evaluate the UPRmt signaling response to acute exercise in skeletal muscle. Male rats were subjected to acute treadmill exercise at 25 m/min for 60 min on a 0 % grade. Plantaris muscles were collected from both sedentary and exercise groups at various times: immediately (0), and at 1, 3, 6, 12, and 24 h post-exercise. Reactive oxygen species (ROS) production was assessed using hydrogen peroxide assay and dihydroethidium staining. Additionally, the mRNA and protein expression of UPRmt markers were measured using ELISA and real-time PCR. Mitochondrial activity was assessed using succinate dehydrogenase (SDH) and cytochrome c oxidase (COX) staining. Our results demonstrated that acute exercise increased ROS production and upregulated UPRmt markers at both gene and protein levels. Moreover, skeletal muscle exhibited an increase in mitochondrial activity in response to exercise, as indicated by SDH and COX staining. These findings suggest that acute treadmill exercise is sufficient to induce ROS production, activate UPRmt signaling, and enhance mitochondrial activity in skeletal muscle, expanding our understanding of mitochondrial adaptations to exercise.

Bone cancer pain (BCP) significantly impacts patients' overall quality of life. Cellular energy metabolism homeostasis is critically dependent on mitochondrial integrity, and emerging evidence suggests that mitochondrial dysfunction in chronic BCP exacerbates pain progression by disrupting nociceptive signaling pathways. Notably, G protein-coupled receptors (GPCRs), a major class of membrane receptors, modulate mitochondrial function through diverse molecular mechanisms. In this study, we investigated the role of Mas-related G protein-coupled receptor C (MrgC) in BCP pathogenesis and its regulatory effects on mitochondrial function.

Male C3H/HeN mice were utilized to establish a BCP model. Transmission electron microscopy and flow cytometry were employed to assess changes in mitochondrial ultrastructure, as well as levels of mtROS, ATP, and MMP in mice experiencing BCP. Following intrathecal injection of BAM8-22, we analyzed the effects of activated MrgC on mitochondrial unfolded protein response (UPRmt)-related molecules (ATF5, HSP60, LONP1, CLPP) and pain-related behaviors in BCP mice. The regulatory mechanism of MrgC on UPRmt was further explored in N2a and 293T cells.

Mice with bone cancer pain showed improved mRNA and protein levels of UPRmt-related molecules, increased MMP and ATP, decreased mitochondrial ROS levels in the spinal cord after receiving an intrathecal injection of BAM8-22. Additionally, the paw withdrawal mechanical threshold in BCP mice increased, while the number of spontaneous foot lifts decreased. In complementary cellular studies, transfection-mediated overexpression of MrgC in N2a cells enhanced UPRmt biomarker expression, whereas RNA interference-mediated MrgC knockdown produced the opposite effect.

By activating spinal MrgC to mediate UPRmt activity and protect mitochondrial function, BAM8-22 contributes to the molecular development of BCP. This discovery suggests a new therapeutic target for BCP and offers a possible research avenue.

Aging biomarkers quantify aging progression and provide actionable targets for therapeutic interventions to mitigate age-related decline. This review synthesizes emerging evidence on testicular aging biomarkers, focusing on cellular senescence (Leydig, Sertoli, and endothelial cells), protein homeostasis disruption, mitochondrial dysfunction, germ stem cell depletion, sperm telomere length, epigenetic alterations, oxidative stress, inflammation, and gut microbiota dysbiosis. We propose that testicular aging serves as a critical nexus linking reproductive decline with systemic aging processes, with its pathological progression being quantifiable through specific biomarkers including the Leydig, Sertoli, and endothelial cells, INSL3, ribosomal protein RPL39L, sperm telomere length, relative telomere length mitochondrial translocator protein, and sialic acid. By bridging systemic aging paradigms with testis-specific mechanisms, we emphasize the urgency to identify organ-selective biomarkers for targeted interventions, advancing strategies to preserve male fertility and address population aging challenges.

Mitochondrial damage and dysfunction are hallmarks of neuronal injury during cerebral ischemia-reperfusion (I/R). Critical mitochondrial functions including energy production and cell signaling are perturbed during I/R, often exacerbating damage and contributing to secondary injury. The integrity of the mitochondrial proteome is essential for efficient function. Mitochondrial proteostasis is mediated by the cooperative forces of mitophagy and intramitochondrial proteolysis. The aim of this study was to elucidate the patterns of mitochondrial protein dynamics and their key regulators during an in vitro model of neuronal I/R injury. Utilizing the MitoTimer reporter, we quantified mitochondrial protein oxidation and turnover during I/R injury, highlighting a key point at 2 h reoxygenation for aged/oxidized protein turnover. This turnover was found to be mediated by both LONP1-dependent proteolysis and PRKN/parkin-dependent mitophagy. Additionally, the proteostatic response of neuronal mitochondria is influenced by both mitochondrial fusion and fission machinery. Our findings highlight the involvement of both mitophagy and intramitochondrial proteolysis in the response to I/R injury.Abbreviations: cKO: conditional knockout; CLPP: caseinolytic mitochondrial matrix peptidase proteolytic subunit; DIV: days in vitro; DNM1L/DRP1: dynamin 1 like; ETC: electron transport chain; hR: hours after reoxygenation; I/R: ischemia-reperfusion; LONP1: lon peptidase 1, mitochondrial; mtUPR: mitochondrial unfolded protein response; OGD: oxygen glucose deprivation; OGD/R: oxygen glucose deprivation and reoxygenation; OPA1: OPA1 mitochondrial dynamin like GTPase; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; ROI: region of interest; WT: wild-type.

Despite the availability of various antiepileptic treatments, approximately 30 % of epilepsy patients remain refractory to conventional therapies, underscoring the need for neuroprotective strategies. This study investigates the role of GrpEL1 in modulating the mitochondrial unfolded protein response (UPRmt) and its potential protective effects on hippocampal neurons following experimental status epilepticus (SE).

The effects of GrpEL1 were assessed in vivo using a Lithium-pilocarpine rat model of SE and in vitro with glutamate-treated HT22 hippocampal cells. Protein expression and interactions were analyzed by Western blot, immunofluorescence, and co-immunoprecipitation. Neuronal survival was evaluated through Nissl staining. Mitochondrial function was evaluated aggresome formation, mitochondrial membrane potential (MMP) assays, mitochondrial oxygen consumption rate (OCR) measurements, and behavioral assessments using the Morris water maze.

In the SE rat model, mtHSP70 levels were significantly upregulated in mitochondria, while GrpEL1 expression remained relatively stable. Overexpression of GrpEL1 led to a reduction in neuronal damage and improved functional recovery post-SE. In vitro, GrpEL1 overexpression enhanced the GrpEL1-mtHSP70 interaction, reduced the accumulation of misfolded proteins, and decreased neuronal apoptosis. Furthermore, GrpEL1 overexpression mitigated mitochondrial dysfunction by preserving MMP and improving mitochondrial bioenergetics, as evidenced by enhanced mitochondrial OCR.

GrpEL1 plays a crucial role in maintaining mitochondrial proteostasis and mitigating hippocampal neuronal injury following SE by regulating UPRmt. These findings suggest that GrpEL1 may represent a promising target for therapeutic intervention to protect against seizure-induced neurodegeneration.

Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are increasingly linked to mitochondrial dysfunction and neuroinflammation. Central to this link are mitochondrial damage-associated molecular patterns (mtDAMPs), including mitochondrial DNA, ATP, and reactive oxygen species, released during mitochondrial stress or damage. These mtDAMPs activate inflammatory pathways, such as the NLRP3 inflammasome and cGAS-STING, contributing to the progression of neurodegenerative diseases. This review delves into the mechanisms by which mtDAMPs drive neuroinflammation and discusses potential therapeutic strategies targeting these pathways to mitigate neurodegeneration. Additionally, it explores the cross-talk between mitochondria and the immune system, highlighting the complex interplay that exacerbates neuronal damage. Understanding the role of mtDAMPs could pave the way for novel treatments aimed at modulating neuroinflammation and slowing disease progression, ultimately improving patient outcome.

The study aims to explore the fluctuating expression of C/EBP Homologous Protein (CHOP) following rat carotid artery injury and its central role in vascular stenosis. Using in vivo rat carotid artery injury models and in vitro ischemia and hypoxia cell models employing human aortic endothelial cells (HAECs) and vascular smooth muscle cells (T/G HA-VSMCs), a comprehensive investigative framework was established. Histological analysis confirmed intimal hyperplasia in rat models. CHOP expression in vascular tissues was assessed using Western blot and immunohistochemical staining, and its presence in HAECs and T/G HA-VSMCs was determined through RT-PCR and Western blot. The study evaluated HAEC apoptosis, inflammatory cytokine secretion, cell proliferation, and T/G HA-VSMCs migration through Western blot, ELISA, CCK8, and Transwell migration assays. The rat carotid artery injury model revealed substantial fibrous plaque formation and vascular stenosis, resulting in an increased intimal area and plaque-to-lumen area ratio. Notably, CHOP is markedly elevated in vessels of the carotid artery injury model compared to normal vessels. Atorvastatin effectively mitigated vascular stenosis and suppresses CHOP protein expression. In HAECs, ischemia and hypoxia-induced CHOP upregulation, along with heightened TNFα, IL-6, caspase3, and caspase8 levels, while reducing cell proliferation. Atorvastatin demonstrated a dose-dependent suppression of CHOP expression in HAECs. Downregulation of CHOP or atorvastatin treatment led to reduced IL-6 and TNFα secretion, coupled with augmented cell proliferation. Similarly, ischemia and hypoxia conditions increased CHOP expression in T/G HA-VSMCs, which was concentration-dependently inhibited by atorvastatin. Furthermore, significantly increased MMP-9 and MMP-2 concentrations in the cell culture supernatant correlated with enhanced T/G HA-VSMCs migration. However, interventions targeting CHOP downregulation and atorvastatin usage curtailed MMP-9 and MMP-2 secretion and suppressed cell migration. In conclusion, CHOP plays a crucial role in endothelial injury, proliferation, and VSMCs migration during carotid artery injury, serving as a pivotal regulator in post-injury fibrous plaque formation and vascular remodeling. Statins emerge as protectors of endothelial cells, restraining VSMCs migration by modulating CHOP expression.

Unlike other ubiquitin-like family members, UBL5 is structurally and functionally atypical, and a novel role in various biological processes and diseases has been discovered. UBL5 can stabilize the structure of the spliceosome, can promote post-transcriptional processing, and has been implicated in both DNA damage repair and protein unfolding reactions, as well as cellular mechanisms that are frequently exploited by viruses for their own proliferation during viral infections. In addition, UBL5 can inhibit viral infection by binding to the non-structural protein 3 of rice stripe virus and mediating its degradation. Therefore, UBL5 is an important link between viral infections and immunity, and its study will be beneficial for the prevention and treatment of viral infections in the future. However, a review of the current findings on the role of UBL5 in viral infection has not been undertaken. Therefore, in this review, we summarize the recent progress in understanding the functions of UBL5 and discuss its putative role in viral infections.

Mitochondria is the primary target of lead (Pb) in neural cells, and Pb exposure can cause impairment to mitochondrial function and morphology. Recent studies have reported that a conserved cellular stress response, called mitochondrial unfolded protein response (mtUPR), is activated in response to mitochondrial dysfunction and protein misfolding and play protective roles in aging and neurodegeneration, but it's unknown whether mtUPR could protect against Pb-induced neurotoxicity. In this study, we found that sublethal level exposure of PbAc (2.5 μM) could cause mitochondria damage and then activate mtUPR by promoting the expression of mitochondrial proteases (LonP1 and ClpP), molecular chaperone (HSPA1A). ATF5 mediated mtUPR activation as knocking out ATF5 significantly inhibited Pb-induced LonP1 and ClpP expression. Moreover, ATF5 deficiency exacerbated Pb-induced mitochondrial morphological and oxidative phosphorylation (OXPHOS) functional damage, resulting in oxidative stress and ultimately promoting cell death. Conversely, overexpression of ATF5 confers protection against Pb-induced oxidative stress and cell death. Collectively, thess results highlight that mtUPR mediated by ATF5 safeguards against mitochondria damage caused by Pb exposure, providing insights into the development of new strategies for mitigating the Pb neurotoxicity.

Postoperative cognitive dysfunction (POCD) is a frequent neurological complication encountered during the perioperative period with unclear mechanisms and no effective treatments. Recent research into the pathogenesis of POCD has primarily focused on neuroinflammation, oxidative stress, changes in neural synaptic plasticity and neurotransmitter imbalances. Given the high-energy metabolism of neurons and their critical dependency on mitochondria, mitochondrial dysfunction directly affects neuronal function. Additionally, as the primary organelles generating reactive oxygen species, mitochondria are closely linked to the pathological processes of neuroinflammation. Surgery and anesthesia can induce mitochondrial dysfunction, increase mitochondrial oxidative stress, and disrupt mitochondrial quality-control mechanisms via various pathways, hence serving as key initiators of the POCD pathological process. We conducted a review on the role and potential mechanisms of mitochondria in postoperative cognitive dysfunction by consulting relevant literature from the PubMed and EMBASE databases spanning the past 25 years. Our findings indicate that surgery and anesthesia can inhibit mitochondrial respiration, thereby reducing ATP production, decreasing mitochondrial membrane potential, promoting mitochondrial fission, inducing mitochondrial calcium buffering abnormalities and iron accumulation, inhibiting mitophagy, and increasing mitochondrial oxidative stress. Mitochondrial dysfunction and damage can ultimately lead to impaired neuronal function, abnormal synaptic transmission, impaired synthesis and release of neurotransmitters, and even neuronal death, resulting in cognitive dysfunction. Targeted mitochondrial therapies have shown positive outcomes, holding promise as a novel treatment for POCD.

Renal ischemia-reperfusion (I/R) injury is an inevitable complication during renal transplantation and is closely related to patient prognosis. Mitochondrial damage induced oxidative stress is the core link of renal I/R injury. Ligustilide (LIG), a natural compound extracted from ligusticum chuanxiong hort and angelica sinensis, has exhibited the potential to protect mitochondrial function. However, whether LIG can ameliorate renal I/R injury requires further investigation. Delving deeper into the precise targets and mechanisms of LIG's effect on renal I/R injury is crucial.

This study aimed to elucidate the specific mechanism of LIG's protective effect on renal I/R injury.

In this study, an in vivo model of renal ischemia-reperfusion (I/R) injury was developed in mice, along with an in vitro model of hypoxia-reoxygenation (H/R) using human proximal renal tubular epithelial cells (HK-2). To assess the impact of LIG on renal injury, various methods were employed, including serum creatinine (Cr) and blood urea nitrogen (BUN) testing, hematoxylin and eosin (HE) staining, and immunohistochemistry (IHC) for kidney injury molecule-1 (KIM-1). The effects of LIG on oxidative stress were examined using fluorescent probes dihydroethidium (DHE) and dichlorodihydrofluorescein diacetate (DCFH-DA), TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, and flow cytometry. Additionally, the influence of LIG on mitochondrial morphology and function was evaluated through transmission electron microscopy (TEM), Mito Tracker Red CMXRos staining, adenosine triphosphate (ATP) concentration assays, and JC-1 staining. The potential mechanism involving LIG and Sirt3 was explored by manipulating Sirt3 expression through cell transfection.

The results showed that LIG could provide protective function for mitochondria to alleviate oxidative stress induced by renal I/R. Further mechanistic studies indicated that LIG maintained mitochondrial homeostasis by targeting Sirt3.

Our findings demonstrated that LIG alleviated oxidative stress during renal I/R injury through maintaining Sirt3-dependent mitochondrial homeostasis. Overall, our data raised the possibility of LIG as a novel therapy for renal I/R injury.

As one of the most vital organelles within biological cells, mitochondria hold an irreplaceable status and play crucial roles in various diseases. Research and therapies targeting mitochondria have achieved significant progress in numerous conditions. Throughout an organism's lifespan, mitochondrial dynamics persist continuously, and due to their inherent characteristics and various external factors, mitochondria are highly susceptible to damage. This susceptibility is particularly evident during aging, where the decline in biological function is closely intertwined with mitochondrial dysfunction. Despite being an ancient and enigmatic organelle, much remains unknown about mitochondria. Here, we will explore the past and present knowledge of mitochondria, providing a comprehensive review of their intrinsic properties and interactions with nuclear DNA, as well as the challenges and impacts they face during the aging process.

Recent research has illuminated the profound bidirectional communication between the gastrointestinal tract and the brain, furthering our understanding of neurological ailments facilitating possible therapeutic strategies. Technological advancements in high-throughput sequencing and multi-omics have unveiled significant alterations in gut microbiota and their metabolites in various neurological disorders. This review provides a thorough analysis of the role of microbiome-gut-brain axis in neurodegenerative disease pathology, linking it to reduced age-associated proteostasis. We discuss evidences that substantiate the existence of a gut-brain cross talk ranging from early clinical accounts of James Parkinson to Braak's hypothesis. In addition to understanding of microbes, the review particularly entails specific metabolites which are altered in neurodegenerative diseases. The regulatory effects of microbial metabolites on protein clearance mechanisms, proposing their potential therapeutic implications, are also discussed. By integrating this information, we advocate for a combinatory therapeutic strategy that targets early intervention, aiming to restore proteostasis and ameliorate disease progression. This approach not only provides a new perspective on the pathogenesis of neurodegenerative diseases but also highlights innovative strategies to combat the increasing burden of these age-related disorders.

Septic cardiomyopathy is characterized by impaired contractile function and mitochondrial activity dysregulation. Salvianolic acid B (Sal B) is a potent therapeutic compound derived from the traditional Chinese medicine Salvia miltiorrhiza. This study explored the protective effects of Sal B on septic heart injury, emphasizing the mitochondrial unfolded protein response (UPRmt).

An in vivo mouse model of lipopolysaccharide (LPS)-induced heart injury was utilized to assess Sal B's protective role in septic cardiomyopathy. Additionally, cell models stimulated by LPS were developed to investigate the mechanisms of Sal B on UPRmt. Quantitative polymerase chain reaction, western blotting, immunohistochemistry, and immunofluorescence were employed for molecular analysis.

Sal B, administered at doses of 10, 30, and 60 mg/kg, demonstrated protective effects on cardiac contractile function, reduced heart inflammation, and mitigated cardiac injury in LPS-exposed mice. In cardiomyocytes, LPS induced apoptosis, elevated mitochondrial ROS levels, promoted mitochondrial fission, and decreased mitochondrial membrane potential, all of which were alleviated by Sal B. Mechanistically, Sal B was found to induce UPRmt both in vivo and in vitro. ATF5, identified as a UPRmt activator, was modulated by LPS and Sal B, resulting in increased ATF5 expression and its translocation from the cytosol to the nucleus. ATF5-siRNA delivery reversed UPRmt upregulation, exacerbating mitochondrial dysfunction in LPS-stimulated cardiomyocytes and counteracting the mitochondrial function enhancement in Sal B-treated cardiomyocytes.

This study provides evidence that Sal B confers cardiac protection by enhancing UPRmt, highlighting its potential as a therapeutic approach for mitigating mitochondrial dysfunction in septic cardiomyopathy.

Mitochondria, pivotal organelles crucial for energy generation, apoptosis regulation, and cellular metabolism, have spurred remarkable advancements in targeted material development. This review surveys recent breakthroughs in targeted mitochondrial nanomaterials, illuminating their potential in drug delivery, disease management, and biomedical imaging. This review approaches from various application perspectives, introducing the specific applications of mitochondria-targeted materials in cancer treatment, probes and imaging, and diseases treated with mitochondria as a therapeutic target. Addressing extant challenges and elucidating potential therapeutic mechanisms, it also outlines future development trajectories and obstacles. By comprehensively exploring the diverse applications of targeted mitochondrial nanomaterials, this review aims to catalyze innovative treatment modalities and diagnostic approaches in medical research. STATEMENT OF SIGNIFICANCE: This review presents the latest advancements in mitochondria-targeted nanomaterials for biomedical applications, covering diverse fields such as cancer therapy, bioprobes, imaging, and the treatment of various systemic diseases. The novelty and significance of this work lie in its systematic analysis of the intricate relationship between mitochondria and different diseases, as well as the ingenious design strategies employed to harness the therapeutic potential of nanomaterials. By providing crucial insights into the development of mitochondria-targeted nanomaterials and their applications, this review offers a valuable resource for researchers working on innovative treatment modalities and diagnostic approaches. The scientific impact and interest to the readership lie in the identification of promising avenues for future research and the potential for clinical translation of these cutting-edge technologies.

Mitochondria are essential organelles that play critical roles in energy metabolism, apoptosis and various cellular processes. Accumulating evidence suggests that mitochondria are also involved in cancer development and progression. The mitochondrial unfolded protein response (UPRmt) is a complex cellular process that is activated when the protein-folding capacity of the mitochondria is overwhelmed. The core machinery of UPRmt includes upstream regulatory factors, mitochondrial chaperones and proteases. These components work together to eliminate misfolded proteins, increase protein-folding capacity, and restore mitochondrial function. Recent studies have shown that UPRmt is dysregulated in various cancers and contributes to tumor initiation, growth, metastasis, and therapeutic resistance. Considering the pivotal role of the UPRmt in oncogenesis, numerous compounds and synthetic drugs targeting UPRmt-related components induce cancer cell death and suppress tumor growth. In this review, we comprehensively summarize recent studies on the molecular mechanisms of UPRmt activation in C. elegans and mammals and elucidate the conceptual framework, functional aspects, and implications of the UPRmt for cancer therapy. In summary, we paint a developmental landscape of the UPRmt in different types of cancer and offer valuable insights for the development of novel cancer treatment strategies by targeting the UPRmt.

Loss of protein homeostasis (proteostasis) is a common hallmark of aging and age-associated diseases. Considered as the guardian of proteostasis, the proteostasis network (PN) acts to preserve the functionality of proteins during their lifetime. However, its activity declines with age, leading to disease manifestation. While reactive oxygen species (ROS) were traditionally considered culprits in this process, recent research challenges this view. While harmful at high concentrations, moderate ROS levels protect the cell against age-mediated onset of proteotoxicity by activating molecular chaperones, stress response pathways, and autophagy. This review explores the nuanced roles of ROS in proteostasis and discusses the most recent findings regarding the redox regulation of the PN and its potential in extending healthspan and delaying age-related pathologies.

Aging is a complex process that features a functional decline in many organelles. Various factors influence the aging process, such as chromosomal abnormalities, epigenetic changes, telomere shortening, oxidative stress, and mitochondrial dysfunction. Mitochondrial dysfunction significantly impacts aging because mitochondria regulate cellular energy, oxidative balance, and calcium levels. Mitochondrial integrity is maintained by mitophagy, which helps maintain cellular homeostasis, prevents ROS production, and protects against mtDNA damage. However, increased calcium uptake and oxidative stress can disrupt mitochondrial membrane potential and permeability, leading to the apoptotic cascade. This disruption causes increased production of free radicals, leading to oxidative modification and accumulation of mitochondrial DNA mutations, which contribute to cellular dysfunction and aging. Mitochondrial dysfunction, resulting from structural and functional changes, is linked to age-related degenerative diseases. This review focuses on mitochondrial dysfunction, its implications in aging and age-related disorders, and potential anti-aging strategies through targeting mitochondrial dysfunction.

The pursuit of enhanced health during aging has prompted the exploration of various strategies focused on reducing the decline associated with the aging process. A key area of this exploration is the management of mitochondrial dysfunction, a notable characteristic of aging. This review sheds light on the crucial role that small molecules play in augmenting healthy aging, particularly through influencing mitochondrial functions. Mitochondrial oxidative damage, a significant aspect of aging, can potentially be lessened through interventions such as coenzyme Q10, alpha-lipoic acid, and a variety of antioxidants. Additionally, this review discusses approaches for enhancing mitochondrial proteostasis, emphasizing the importance of mitochondrial unfolded protein response inducers like doxycycline, and agents that affect mitophagy, such as urolithin A, spermidine, trehalose, and taurine, which are vital for sustaining protein quality control. Of equal importance are methods for modulating mitochondrial energy production, which involve nicotinamide adenine dinucleotide boosters, adenosine 5'-monophosphate-activated protein kinase activators, and compounds like metformin and mitochondria-targeted tamoxifen that enhance metabolic function. Furthermore, the review delves into emerging strategies that encourage mitochondrial biogenesis. Together, these interventions present a promising avenue for addressing age-related mitochondrial degradation, thereby setting the stage for the development of innovative treatment approaches to meet this extensive challenge.

Hepatocellular carcinoma (HCC) is a common cause of cancer-associated death worldwide. The mitochondrial unfolded protein response (UPRmt) not only maintains mitochondrial integrity but also regulates cancer progression and drug resistance. However, no study has used the UPRmt to construct a prognostic signature for HCC. This work aimed to establish a novel signature for predicting patient prognosis, immune cell infiltration, immunotherapy, and chemotherapy response based on UPRmt-related genes (MRGs). Transcriptional profiles and clinical information were obtained from the TCGA and ICGC databases. Cox regression and LASSO regression analyses were applied to select prognostic genes and develop a risk model. The TIMER algorithm was used to investigate immunocytic infiltration in the high- and low-risk subgroups. Here, two distinct clusters were identified with different prognoses, immune cell infiltration statuses, drug sensitivities, and response to immunotherapy. A risk score consisting of seven MRGs (HSPD1, LONP1, SSBP1, MRPS5, YME1L1, HDAC1 and HDAC2) was developed to accurately and independently predict the prognosis of HCC patients. Additionally, the expression of core MRGs was confirmed by immunohistochemistry (IHC) staining, single-cell RNA sequencing, and spatial transcriptome analyses. Notably, the expression of prognostic MRGs was significantly correlated with sorafenib sensitivity in HCC and markedly downregulated in sorafenib-treated HepG2 and Huh7 cells. Furthermore, the knockdown of LONP1 decreased the proliferation, invasion, and migration of HepG2 cells, suggesting that upregulated LONP1 expression contributed to the malignant behaviors of HCC cells. To our knowledge, this is the first study to investigate the consensus clustering algorithm, prognostic potential, immune microenvironment infiltration and drug sensitivity based on the expression of MRGs in HCC. In summary, the UPRmt-related classification and prognostic signature could assist in determining the prognosis and personalized therapy of HCC patients from the perspectives of predictive, preventative and personalized medicine.

Podocyte injury plays a critical role in the progression of diabetic kidney disease (DKD), but the underlying cellular and molecular mechanisms remain poorly understanding. MicroRNAs (miRNAs) can disrupt gene expression by inducing translation inhibition and mRNA degradation, and recent evidence has shown that miRNAs may play a key role in many kidney diseases. In this study, we identified miR-4645-3p by global transcriptome expression profiling as one of the major downregulated miRNAs in high glucose-cultured podocytes. Moreover, whether DKD patients or STZ-induced diabetic mice, expression of miR-4645-3p was also significantly decreased in kidney. In the podocytes cultured by normal glucose, inhibition of miR-4645-3p expression promoted mitochondrial damage and podocyte apoptosis. In the podocytes cultured by high glucose (30 mM glucose), overexpression of miR-4645-3p significantly attenuated mitochondrial dysfunction and podocyte apoptosis induced by high glucose. Furthermore, we found that miR-4645-3p exerted protective roles by targeting Cdk5 inhibition. In vitro, miR-4645-3p obviously antagonized podocyte injury by inhibiting overexpression of Cdk5. In vivo of diabetic mice, podocyte injury, proteinuria, and impaired renal function were all effectively ameliorated by treatment with exogenous miR-4645-3p. Collectively, these findings demonstrate that miR-4645-3p can attenuate podocyte injury and mitochondrial dysfunction in DKD by targeting Cdk5. Sustaining the expression of miR-4645-3p in podocytes may be a novel strategy to treat DKD.

In this investigation, we administered oxidative stress to nucleus pulposus cells (NPCs), recognized DNA-damage-inducible transcript 4 (DDIT4) as a component in intervertebral disc degeneration (IVDD), and devised a hydrogel capable of conveying small interfering RNA (siRNA) to IVDD.

An in vitro model for oxidative stress-induced injury in NPCs was developed to elucidate the mechanisms underlying the upregulation of DDIT4 expression, activation of the reactive oxygen species (ROS)-thioredoxin-interacting protein (TXNIP)-NLRP3 signalling pathway, and nucleus pulposus pyroptosis. Furthermore, the mechanism of action of small interfering DDIT4 (siDDIT4) on NPCs in vitro was validated. A triplex hydrogel named siDDIT4@G5-P-HA was created by adsorbing siDDIT4 onto fifth-generation polyamidoamine (PAMAM) dendrimer using van der Waals interactions, and then coating it with hyaluronic acid (HA). In addition, we established a rat puncture IVDD model to decipher the hydrogel's mechanism in IVDD.

A correlation between DDIT4 expression levels and disc degeneration was shown with human nucleus pulposus and needle-punctured rat disc specimens. We confirmed that DDIT4 was responsible for activating the ROS-TXNIP-NLRP3 axis during oxidative stress-induced pyroptosis in rat nucleus pulposus in vitro. Mitochondria were damaged during oxidative stress, and DDIT4 contributed to mitochondrial damage and ROS production. In addition, siDDIT4@G5-P-HA hydrogels showed good delivery activity of siDDIT4 to NPCs. In vitro studies illustrated the potential of the siDDIT4@G5-P-HA hydrogel for alleviating IVDD in rats.

DDIT4 is a key player in mediating pyroptosis and IVDD in NPCs through the ROS-TXNIP-NLRP3 axis. Additionally, siDDIT4@G5-P-HA hydrogel has been found to relieve IVDD in rats. Our research offers an innovative treatment option for IVDD.

Lipotoxicity arises from the accumulation of lipid intermediates in non-adipose tissue, precipitating cellular dysfunction and death. Ceramide, a toxic byproduct of excessive free fatty acids, has been widely recognized as a primary contributor to lipotoxicity, mediating various cellular processes such as apoptosis, differentiation, senescence, migration, and adhesion. As the hub of lipid metabolism, the excessive accumulation of ceramides inevitably imposes stress on the mitochondria, leading to the disruption of mitochondrial homeostasis, which is typified by adequate ATP production, regulated oxidative stress, an optimal quantity of mitochondria, and controlled mitochondrial quality. Consequently, this review aims to collate current knowledge and facts regarding the involvement of ceramides in mitochondrial energy metabolism and quality control, thereby providing insights for future research.

The incidence and mortality rates of colorectal cancer have elevated its status as a significant public health concern. Recent research has elucidated the crucial role of mitochondrial fusion-fission dynamics in the initiation and progression of colorectal cancer. Elevated mitochondrial fission or fusion activity can contribute to the metabolic reprogramming of tumor cells, thereby activating oncogenic pathways that drive cell proliferation, invasion, migration, and drug resistance. Nevertheless, excessive mitochondrial fission can induce apoptosis, whereas moderate mitochondrial fusion can protect cells from oxidative stress. This imbalance in mitochondrial dynamics can exert dual roles as both promoters and inhibitors of colorectal cancer progression. This review provides an in-depth analysis of the fusion-fission dynamics and the underlying pathological mechanisms in colorectal cancer cells. Additionally, it offers partial insights into the mitochondrial kinetics in colorectal cancer-associated cells, such as immune and endothelial cells. This review is aimed at identifying key molecular events involved in colorectal cancer progression and highlighting the potential of mitochondrial dynamic proteins as emerging targets for pharmacological intervention.

Type 2 diabetes mellitus (T2DM) poses a significant global health burden. This is particularly due to its macrovascular complications, such as coronary artery disease, peripheral vascular disease, and cerebrovascular disease, which have emerged as leading contributors to morbidity and mortality. This review comprehensively explores the pathophysiological mechanisms underlying these complications, protective strategies, and both existing and emerging secondary preventive measures. Furthermore, we delve into the applications of experimental models and methodologies in foundational research while also highlighting current research limitations and future directions. Specifically, we focus on the literature published post-2020 concerning the secondary prevention of macrovascular complications in patients with T2DM by conducting a targeted review of studies supported by robust evidence to offer a holistic perspective.

The serine peptidase CLPP is conserved among bacteria, chloroplasts, and mitochondria. In humans and mice, its loss causes Perrault syndrome, which presents with growth deficits, infertility, deafness, and ataxia. In the filamentous fungus Podospora anserina, CLPP loss leads to longevity. CLPP substrates are selected by CLPX, an AAA+ unfoldase. CLPX is known to target delta-aminolevulinic acid synthase (ALAS) to promote pyridoxal phosphate (PLP) binding. CLPX may also influence cofactor association with other enzymes. Here, the evaluation of P. anserina metabolomics highlighted a reduction in arginine/histidine levels. In Mus musculus cerebellum, reductions in arginine/histidine and citrulline occurred with a concomitant accumulation of the heme precursor protoporphyrin IX. This suggests that the increased biosynthesis of 5-carbon (C5) chain deltaALA consumes not only C4 succinyl-CoA and C1 glycine but also specific C5 delta amino acids. As enzymes responsible for these effects, the elevated abundance of CLPX and ALAS is paralleled by increased OAT (PLP-dependent, ornithine delta-aminotransferase) levels. Possibly as a consequence of altered C1 metabolism, the proteome profiles of P. anserina CLPP-null cells showed strong accumulation of a methyltransferase and two mitoribosomal large subunit factors. The reduced histidine levels may explain the previously observed metal interaction problems. As the main nitrogen-storing metabolite, a deficiency in arginine would affect the urea cycle and polyamine synthesis. Supplementation of arginine and histidine might rescue the growth deficits of CLPP-mutant patients.

Stroke is a clinical syndrome characterized by an acute, focal neurological deficit, primarily caused by the occlusion or rupture of cerebral blood vessels. In stroke, neuroinflammation emerges as a pivotal event contributing to neuronal cell death. The occurrence and progression of neuroinflammation entail intricate processes, prominently featuring mitochondrial dysfunction and adaptive responses. Mitochondria, a double membrane-bound organelle are recognized as the "energy workshop" of the body. Brain is particularly vulnerable to mitochondrial disturbances due to its high energy demands from mitochondria-related energy production. The interplay between mitochondria and neuroinflammation plays a significant role in the pathogenesis of stroke. The biological and pathological consequences resulting from mitochondrial stress have substantial implications for cerebral function. Mitochondrial stress serves as an adaptive mechanism aimed at mitigating the stress induced by the import of misfolded proteins, which occurs in response to stroke. This adaptive response involves a reduction in misfolded protein accumulation and overall protein synthesis. The influence of mitochondrial stress on the pathological state of stroke is underscored by its capacity to interact with neuroinflammation. The impact of mitochondrial stress on neuroinflammation varies according to its severity. Moderate mitochondrial stress can bolster cellular adaptive defenses, enabling cells to better withstand detrimental stressors. In contrast, sustained and excessive mitochondrial stress detrimentally affects cellular and tissue integrity. The relationship between neuroinflammation and mitochondrial stress depends on the degree of mitochondrial stress present. Understanding its role in stroke pathogenesis is instrumental in excavating the novel treatment of stroke. This review aims to provide the evaluation of the cross-talk between mitochondrial stress and neuroinflammation within the context of stroke. We aim to reveal how mitochondrial stress affects neuroinflammation environment in stroke.

Colorectal cancer (CRC) is a significant public health concern, and its development is associated with mitochondrial dysfunction. Mitochondria can adapt to the high metabolic demands of cancer cells owing to their plasticity and dynamic nature. The fusion-fission dynamics of mitochondria play a crucial role in signal transduction and metabolic functions of CRC cells. Enhanced mitochondrial fission promotes the metabolic reprogramming of CRC cells, leading to cell proliferation, metastasis, and chemoresistance. Excessive fission can also trigger mitochondria-mediated apoptosis. In contrast, excessive mitochondrial fusion leads to adenosine triphosphate (ATP) overproduction and abnormal tumor proliferation, whereas moderate fusion protects intestinal epithelial cells from oxidative stress-induced mitochondrial damage, thus preventing colitis-associated cancer (CAC). Therefore, an imbalance in mitochondrial dynamics can either promote or inhibit CRC progression. This review provides an overview of the mechanism underlying mitochondrial fusion-fission dynamics and their impact on CRC biology. This revealed the dual role of mitochondrial fusion-fission dynamics in CRC development and identified potential drug targets. Additionally, this study partially explored mitochondrial dynamics in immune and vascular endothelial cells in the tumor microenvironment, suggesting promising prospects for targeting key fusion/fission effector proteins against CRC.

Synapses serve as the points of communication between neurons, consisting primarily of three components: the presynaptic membrane, synaptic cleft, and postsynaptic membrane. They transmit signals through the release and reception of neurotransmitters. Synaptic plasticity, the ability of synapses to undergo structural and functional changes, is influenced by proteins such as growth-associated proteins, synaptic vesicle proteins, postsynaptic density proteins, and neurotrophic growth factors. Furthermore, maintaining synaptic plasticity consumes more than half of the brain's energy, with a significant portion of this energy originating from ATP generated through mitochondrial energy metabolism. Consequently, the quantity, distribution, transport, and function of mitochondria impact the stability of brain energy metabolism, thereby participating in the regulation of fundamental processes in synaptic plasticity, including neuronal differentiation, neurite outgrowth, synapse formation, and neurotransmitter release. This article provides a comprehensive overview of the proteins associated with presynaptic plasticity, postsynaptic plasticity, and common factors between the two, as well as the relationship between mitochondrial energy metabolism and synaptic plasticity.

Mitochondria play a key role in cellular functions, including energy production and oxidative stress regulation. For this reason, maintaining mitochondrial homeostasis and proteostasis (homeostasis of the proteome) is essential for cellular health. Therefore, there are different mitochondrial quality control mechanisms, such as mitochondrial biogenesis, mitochondrial dynamics, mitochondrial-derived vesicles (MDVs), mitophagy, or mitochondrial unfolded protein response (mtUPR). The last item is a stress response that occurs when stress is present within mitochondria and, especially, when the accumulation of unfolded and misfolded proteins in the mitochondrial matrix surpasses the folding capacity of the mitochondrion. In response to this, molecular chaperones and proteases as well as the mitochondrial antioxidant system are activated to restore mitochondrial proteostasis and cellular function. In disease contexts, mtUPR modulation holds therapeutic potential by mitigating mitochondrial dysfunction. In particular, in the case of neurodegenerative diseases, such as primary mitochondrial diseases, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic Lateral Sclerosis (ALS), or Friedreich's Ataxia (FA), there is a wealth of evidence demonstrating that the modulation of mtUPR helps to reduce neurodegeneration and its associated symptoms in various cellular and animal models. These findings underscore mtUPR's role as a promising therapeutic target in combating these devastating disorders.

Myocardial damage is the most serious pathological consequence of cardiovascular diseases and an important reason for their high mortality. In recent years, because of the high prevalence of systemic energy metabolism disorders (e.g., obesity, diabetes mellitus, and metabolic syndrome), complications of myocardial damage caused by these disorders have attracted widespread attention. Energy metabolism disorders are independent of traditional injury-related risk factors, such as ischemia, hypoxia, trauma, and infection. An imbalance of myocardial metabolic flexibility and myocardial energy depletion are usually the initial changes of myocardial injury caused by energy metabolism disorders, and abnormal morphology and functional destruction of the mitochondria are their important features. Specifically, mitochondria are the centers of energy metabolism, and recent evidence has shown that decreased mitochondrial function, caused by an imbalance in mitochondrial quality control, may play a key role in myocardial injury caused by energy metabolism disorders. Under chronic energy stress, mitochondria undergo pathological fission, while mitophagy, mitochondrial fusion, and biogenesis are inhibited, and mitochondrial protein balance and transfer are disturbed, resulting in the accumulation of nonfunctional and damaged mitochondria. Consequently, damaged mitochondria lead to myocardial energy depletion and the accumulation of large amounts of reactive oxygen species, further aggravating the imbalance in mitochondrial quality control and forming a vicious cycle. In addition, impaired mitochondria coordinate calcium homeostasis imbalance, and epigenetic alterations participate in the pathogenesis of myocardial damage. These pathological changes induce rapid progression of myocardial damage, eventually leading to heart failure or sudden cardiac death. To intervene more specifically in the myocardial damage caused by metabolic disorders, we need to understand the specific role of mitochondria in this context in detail. Accordingly, promising therapeutic strategies have been proposed. We also summarize the existing therapeutic strategies to provide a reference for clinical treatment and developing new therapies.

Postoperative cognitive dysfunction (POCD) is a common surgical complication that causes additional pain in patients and affects their quality of life. To address this problem, emerging studies have focused on the POCD. Recent studies have shown that aging and anesthetic exposure are the two major risk factors for developing POCD. However, few reports described the exact molecular mechanisms underlying POCD in elderly patients. In the previous studies, the endoplasmic reticulum (ER) stress and neuroapoptosis in the hippocampus were associated with inducing POCD; however, no further information on the related signaling pathways could be disclosed. The PERK-eIF2α-ATF4-CHOP pathway is identified as the main regulatory pathway involved in ER stress and cell apoptosis. Therefore, we assume that the occurrence of POCD induced by sevoflurane inhalation may potentially result from ER stress and neuroapoptosis in the hippocampus of aged mice mediated by the PERK-eIF2α-ATF4-CHOP pathway. In our study, we found a relationship between sevoflurane inhalation concentration and memory decline in aged mice, with a 'ceiling effect'. We have confirmed that POCD induced by sevoflurane results from ER stress and neuroapoptosis in the hippocampus of aged mice, which is regulated by the over-expression of PERK-eIF2α-ATF4-CHOP pathway. Furthermore, we also showed that the dephosphorylation inhibitor of eIF2α (salubrinal) could down-regulate PERK-eIF2α-ATF4-CHOP pathway expression to inhibit ER stress and enhance the cognitive function of aged mice. In general, our study has elucidated one of the molecular mechanisms of sevoflurane-related cognitive dysfunction in aged groups and provided new strategies for treating sevoflurane-induced POCD.

Various models of mitochondrial stress result in induction of the stress-responsive cytokines fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15). This is an adaptive mechanism downstream of the mitochondrial integrated stress response frequently associated with improvements in systemic metabolic health. Both FGF21 and GDF15 have been shown to modulate energy balance and glucose homeostasis, and their pharmacological administration leads to promising beneficial effects against obesity and associated metabolic diseases in pre-clinical models. Furthermore, endogenous upregulation of FGF21 and GDF15 is associated with resistance to diet-induced obesity (DIO), improved glucose homeostasis and increased insulin sensitivity. In this review, we highlight several studies on transgenic mouse models of mitochondrial stress and will compare the specific roles played by FGF21 and GDF15 on the systemic metabolic adaptations reported in these models.

CUT homeobox genes represent a captivating gene class fulfilling critical functions in the development and maintenance of multiple cell types across a wide range of organisms. They belong to the larger group of homeobox genes, which encode transcription factors responsible for regulating gene expression patterns during development. CUT homeobox genes exhibit two distinct and conserved DNA binding domains, a homeodomain accompanied by one or more CUT domains. Numerous studies have shown the involvement of CUT homeobox genes in diverse developmental processes such as body axis formation, organogenesis, tissue patterning and neuronal specification. They govern these processes by exerting control over gene expression through their transcriptional regulatory activities, which they accomplish by a combination of classic and unconventional interactions with the DNA. Intriguingly, apart from their roles as transcriptional regulators, they also serve as accessory factors in DNA repair pathways through protein-protein interactions. They are highly conserved across species, highlighting their fundamental importance in developmental biology. Remarkably, evolutionary analysis has revealed that CUT homeobox genes have experienced an extraordinary degree of rearrangements and diversification compared to other classes of homeobox genes, including the emergence of a novel gene family in vertebrates. Investigating the functions and regulatory networks of CUT homeobox genes provides significant understanding into the molecular mechanisms underlying embryonic development and tissue homeostasis. Furthermore, aberrant expression or mutations in CUT homeobox genes have been associated with various human diseases, highlighting their relevance beyond developmental processes. This review will overview the well known roles of CUT homeobox genes in nervous system development, as well as their functions in other tissues across phylogeny.