Mitochondria-targeted Therapy Research Articles

Mitochondrial Dysfunction in Congenital Heart Disease

Mitochondria play a crucial role in multiple cellular processes such as energy metabolism, generation of reactive oxygen species, excitation–contraction coupling, cell survival and death. Dysfunction of mitochondria contributes to the development of cancer; neuromuscular, cardiovascular/congenital heart disease; and metabolic diseases, including diabetes. Mitochondrial dysfunction can result in excessive reactive oxygen species, a decrease in energy production, mitophagy and apoptosis. All these processes are known to be dysregulated in cardiovascular diseases. The focus of this review is to summarize our current knowledge of mitochondrial dysfunction, including mitophagy and apoptosis, in pediatric congenital heart disease due to maternal diabetes or due to structural cardiac defects, with a focus on single-ventricle congenital heart disease. We also discuss recent mitochondria-targeted therapies for cardiovascular diseases.

In Situ Transformable Nanoparticle Effectively Suppresses Bladder Cancer by Damaging Mitochondria and Blocking Mitochondrial Autophagy Flux.

Tumor therapeutic strategies based on mitochondrial damage have become an emerging trend. However, the low drug delivery efficiency caused by lysosomal sequestration and the activation of protective mitochondrial autophagy severely restricts the therapeutic efficacy. Herein, an in situ transformable nanoparticle named KCKT is developed to promote lysosomal escape and directly damage mitochondria while blocking mitochondrial autophagy. KCKT exhibits acid responsiveness for precise self-assembly into nanofibers within the lysosomes of cancer cells. The massive accumulation of nanofibers and excessive production of reactive oxygen species (ROS) under sonodynamic therapy synergistically induce lysosomal damage. This facilitates the escape of nanofibers from lysosomal sequestration, thereby enhancing drug delivery. Subsequently, the escaped nanofibers specifically aggregate around the mitochondria for long-term retention and generate ROS under ultrasound irradiation to induce mitochondrial damage. Notably, due to lysosomal dysfunction, damaged mitochondria cannot be cleared by autophagy, further aggravating oxidative damage. These results reveal that KCKT effectively improves drug delivery and mitochondria-targeted therapy efficiency by blocking protective autophagy. These findings hold significant potential for advancing the field of mitochondria-targeted therapy.

Advances in research on the relationship between mitochondrial function and colorectal cancer: a bibliometric study from 2013 to 2023.

The study provides a thorough examination of literature from 2013 to 2023, delving into the intricate relationship between mitochondrial function and colorectal cancer (CRC). It offers a concise overview of the current landscape and emerging trends in this rapidly evolving research area. The findings indicate a consistent rise in annual publications, reflecting growing interest and significant potential in the field. China emerges as the leading contributor, followed by the United States and India. However, despite China's dominance in output, its average citation rate is lower than that of the US, which leads in citations per publication, highlighting a noticeable disparity. In the realm of research institutions, Shanghai Jiao Tong University and China Medical University are identified as major contributors, yet the potential for inter-institutional collaboration remains largely untapped, suggesting avenues for future synergy. Internationally, China-US collaborations are particularly robust, fostering cross-border knowledge exchange. Hyun Jin Won and Li Wei are recognized as prolific authors, while Ahmedin Jemal is an influential co-cited scholar, noted for his seminal contributions. Keyword analysis reveals research focus areas, such as the complex CRC tumor microenvironment, molecular mechanisms of oxidative stress, and key multidrug resistance pathways. It also highlights the promising potential of mitochondria-targeted therapies and nanomolecular technologies in clinical practice, signaling their growing significance in addressing complex health challenges. The study underscores the imperative to validate complex mitochondrial mechanisms and signaling pathways in CRC, with a particular emphasis on translating these insights into drug targets for clinical trials. Advancing this research is expected to refine and enhance CRC treatment strategies. Additionally, it highlights the urgency of validating mitochondrial complexities in CRC, advocating for collaborative efforts to link these mechanisms with tailored therapeutic interventions for clinical testing. This integrated approach promises significant advancements in developing effective, targeted CRC treatments, ultimately improving patient outcomes.

Small Molecules Targeting Mitochondria: A Mechanistic Approach to Combating Doxorubicin-Induced Cardiotoxicity.

Doxorubicin (Dox) is a commonly used chemotherapy drug effective against a range of cancers, but its clinical application is greatly limited by dose-dependent and cumulative cardiotoxicity. Mitochondrial dysfunction is recognized as a key factor in Dox-induced cardiotoxicity, leading to oxidative stress, disrupted calcium balance, and activation of apoptotic pathways. Recent research has emphasized the potential of small molecules that specifically target mitochondria to alleviate these harmful effects. This review provides a comprehensive analysis of small molecules that offer cardioprotection by preserving mitochondrial function in the context of doxorubicin-induced cardiotoxicity (DIC). The mechanisms of action include the reduction of reactive oxygen species (ROS) production, stabilization of mitochondrial membrane potential, enhancement of mitochondrial biogenesis, and modulation of key signaling pathways involved in cell survival and apoptosis. By targeting mitochondria, these small molecules present a promising therapeutic strategy to prevent or reduce the cardiotoxic effects associated with Dox treatment. This review not only discusses the mechanistic actions of these agents but also emphasizes their potential in improving cardiovascular outcomes for cancer patients. Gaining insight into these mechanisms can help in creating more effective strategies to safeguard the heart during chemotherapy, allowing for the ongoing use of Dox with a lower risk to the patient's cardiovascular health. This review highlights the critical role of mitochondria-targeted therapies as a promising approach in addressing DIC.

The clinical efficacy of cGMP-specific sildenafil on mitochondrial biogenesis induction and renal damage in cats with acute on chronic kidney disease

BackgroundMitochondrial biogenesis (MB) induction has recently emerged as potential therapeutic approaches in kidney pathology and the mitochondria-targeted therapies should be investigated to improve treatment of animals with kidney diseases. This study aimed to investigate the effects of MB induction with sildenafil citrate on the cGMP/NO pathway, glomerular filtration, and reduction of kidney damage and fibrosis (TGF-β/SMAD pathway) in cats with acute on chronic kidney disease (ACKD). Thirty-three cats were divided into the non-azotemic (healthy) group (n:8) and the ACKD group (n:25), comprising different breeds, sexes, and ages. Sildenafil citrate was administered to the non-azotemic and ACKD groups (2.5 mg/kg, PO, q12 hours) for 30 days. Serum and urine NO, MDA, NGAL, KIM-1, TGF-β1, IL-18, FGF 23, PGC-1α and cGMP concentrations were measured.ResultsSerum cGMP concentrations increased (P < 0.05) in the non-azotemic group during the 2nd (median 475.99 pmol/mL) and 3rd (median 405.01 pmol/mL) weeks of the study, whereas serum cGMP concentrations decreased in the ACKD group during the 4th(median 188.52 pmol/mL) week compared to the non-azotemic group (P < 0.05). No difference was observed in serum biomarker concentrations except NO, which increased in the 4th week (P < 0.05). The urinary concentrations of NO, MDA, PGC-1α, TGF-β1, NGAL, KIM-1, IL-18, and FGF 23 in the ACKD group were found to be higher compared to those in the non-azotemic group from the 1st to the 4th week (P < 0.05). In the ACKD group, the urine PGC-1α concentration in the 2nd (median 6.10 ng/mL) week was lower compared to that in the 0 and 1st (median 7.65 and 7.21 ng/mL, respectively) week, and the NO concentration in the 3rd (median 28.94 µmol/mL) week was lower than that in the 0th (median 37.43 µmol/mL) week (P < 0.05).ConclusionsWhile sildenafil citrate has been determined to induce a low level of MB and to have a beneficial effect on glomerular filtration, it is observed to be ineffective in mitigating renal damage and fibrosis via the TGF-β/SMAD pathway in cats with ACKD.

Novel mitochondria-targeted therapy AP39 limits mitochondrial dysregulation and diastolic dysfunction in 2D &amp; 3D human models of diabetic cardiomyopathy

Abstract Introduction Mitochondrial dysregulation has been implicated in many complications of diabetes. Mitochondrial-targeted therapies AP39 and SS31 are renoprotective, but their cardioprotective potential in diabetes has not been fully resolved. Purpose We investigated AP39 and SS31 in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-hCM) and endothelial cells (iPSC-hEC) independently in 2D culture, as well as collectively in a 3D cardiac organoid (iPSC-hCO) model also comprising fibroblasts (iPSC-hFB), under type 2 diabetes (T2D)-like conditions. Methods Cells (iPSC-hCM, iPSC-hEC, iPSC-hFB; foreskin-2 cell line) were exposed to either 5.55mM glucose (control) or T2D conditions (20mM glucose plus fatty acids, endothelin-1 and cortisol) ± AP39 (50nM) or SS31 (1µM) for 48h. Cardiac organoids were subjected to 5.55mM glucose (control) or T2D for 4 days, with AP39 (50nM) or SS31 (1µM) added on day 2. Data are expressed as mean±SEM (fold) with n=4-6 from 2-3 independent experiments. One-way ANOVA with Dunnett`s post hoc analysis was performed with P&amp;lt;0.05 considered significant. Results 2D human cells: After 48h, T2D increased mitochondrial superoxide in iPSC-hCM (2.4±0.1 fold vs control) and iPSC-hEC (3.2±0.29 fold vs control), both P&amp;lt;0.05 (measured by MitoSOX). This was blunted by both AP39 (to 1.1±0.17) and SS31 (to 1.5±0.17) in T2D iPSC-hCM (P&amp;lt;0.05), with similar impact in iPSC-hEC, to 2.9±0.26 and 1.3±0.16 fold, both P&amp;lt;0.05. T2D increased cell death in both iPSC-hCM (1.6±0.09 fold vs control) and iPSC-hEC (1.6±0.12 fold, both P&amp;lt;0.05 measured by propidium iodide staining. Interestingly, AP39 selectively blunted cell death in T2D iPSC-hCM (to 1.1±0.06, P&amp;lt;0.05), mimicked by SS31 in T2D iPSC-hEC only (to 1.0±0.10, P&amp;lt;0.05). Further, T2D-induced mitochondrial hyperpolarisation in iPSC-hCM (1.5±0.09 fold vs control, assessed using TMRM), was only protected by AP39 (1.2±0.06 fold, P&amp;lt;0.05), but not SS31. 3D human cardiac organoids: After 4 days, T2D increased total contraction duration (1.6±0.10 fold control), time to peak (1.7±0.11) and relaxation duration (1.5±0.13, indicative of diastolic dysfunction), assessed by Olympus IX71 with a DP72 camera. All 3 contractile parameters were attenuated with AP39 (to 1.5±0.06, 1.3±0.09 and 1.0±0.04 fold, respectively) or SS31 (to 1.1±0.05, 1.2±0.15 and 1.2±0.12 fold, respectively), all P&amp;lt;0.05. T2D increased mitochondrial superoxide (2.7±0.16 fold control), blunted by AP39 (to 1.8±0.16) and SS31 (to 1.9±0.17), both P&amp;lt;0.05. Cellular injury measured by LDH was evident in T2D iPSC-hCO (2.1±0.23 fold control) was limited by AP39 (to 1.2±0.09) and SS31 (to 1.1±0.07), both P&amp;lt;0.05. Conclusion Our results highlight the cardioprotective potential of AP39 and SS31 to limit mitochondrial dysregulation, cell death and contractile dysfunction in human in vitro models of T2D. These findings may facilitate their clinical progression as therapeutic options for diabetic cardiomyopathy.

Prospective Intervention Strategies Between Skeletal Muscle Health and Mitochondrial Changes During Aging.

Sarcopenia is a geriatric condition characterized by a decrease in skeletal muscle mass and function, significantly impacting both quality of life and overall health. Mitochondria are the main sites of energy production within the cell, and also produce reactive oxygen species (ROS), which maintain mitochondrial homeostasis-mitophagy (clearing damaged mitochondria); mitochondrial dynamics, which involve fusion and fission to regulate mitochondrial morphology; mitochondrial biogenesis, which ensures the functionality and homeostasis of mitochondria. Sarcopenia is linked to mitochondrial dysfunction, suggesting that muscle mitochondrial function therapy should be investigated. Extrinsic therapies are extensively examined to identify new treatments for muscular illnesses including sarcopenia. Changes in muscle physiology and lifestyle interventions, such as pharmacological treatments and exercise, can modulate mitochondrial activity in older adults. This PubMed review encompasses the most significant mitophagy and sarcopenia research from the past five years. Animal models, cellular models, and human samples are well covered. The review will inform the development of novel mitochondria-targeted therapies aimed at combating age-related muscle atrophy.

Mitochondrial signaling pathways and their role in cancer drug resistance

Mitochondria, traditionally known as cellular powerhouses, now emerge as critical signaling centers influencing cancer progression and drug resistance. The review highlights the role that apoptotic signaling, DNA mutations, mitochondrial dynamics and metabolism play in the development of resistance mechanisms and the advancement of cancer. Targeted approaches are discussed, with an emphasis on managing mitophagy, fusion, and fission of the mitochondria to make resistant cancer cells more susceptible to traditional treatments. Additionally, metabolic reprogramming can be used to effectively target metabolic enzymes such GLUT1, HKII, PDK, and PKM2 in order to avoid resistance mechanisms. Although there are potential possibilities for therapy, the complex structure of mitochondria and their subtle role in tumor development hamper clinical translation. Novel targeted medicines are put forth, providing fresh insights on combating drug resistance in cancer. The study also emphasizes the significance of glutamine metabolism, mitochondrial respiratory complexes, and apoptotic pathways as potential targets to improve treatment effectiveness against drug-resistant cancers. Combining complementary and nanoparticle-based techniques to target mitochondria has demonstrated encouraging results in the treatment of cancer, opening doors to reduce resistance and enable individualized treatment plans catered to the unique characteristics of each patient. Suggesting innovative approaches such as drug repositioning and mitochondrial drug delivery to enhance the efficacy of mitochondria-targeting therapies, presenting a pathway for advancements in cancer treatment. This thorough investigation is a major step forward in the treatment of cancer and has the potential to influence clinical practice and enhance patient outcomes.

AB029. Mitochondrial dysfunction and impaired growth of glioblastoma cell lines caused by antimicrobial agents inducing ferroptosis.

Glioblastoma, a malignant tumor, has no curative treatment. Mitochondria have been reported to be involved in tumorigenesis and drug resistance in various cancers. Recently, mitochondria have been considered a potential target for treating glioblastoma. We are developing a new treatment for glioblastoma targeting mitochondria. The microenvironment of glioblastoma is reported to be a low-nutrition and hypoxic condition. We focused our research on how mitochondria work under tumor circumstances. In this research, we used cell lines including U87, LN229, U373, T98G, and two patient-derived stem-like cells. First, we investigated the efficacy of mitochondria-targeted glioblastoma therapy in cell lines under glucose-starved conditions and the mechanism of cell death caused by mitochondria-targeted therapy. Second, we developed a treatment effective for cells with more glucose, because we believe that there is some lesion with higher glucose concentration in the tumor considering the heterogeneity of the tumor. We discovered that under glucose-starved conditions, mitochondria-related proteins and oxidative phosphorylation activity increased in glioblastoma cells, and in this condition, glioblastoma cells strongly depended on mitochondria. Administration of agents causing mitochondrial dysfunction including chloramphenicol was very effective and it led to cell death. The mechanism of cell death was not apoptosis but ferroptosis which is a recently discovered type of cell death caused by iron accumulation. In normoglycemic conditions, the effect of chloramphenicol was poor for the short term, however, for the long term, it was effective and caused cell death. Although both chloramphenicol alone and combined treatment using 2-DG (glycolysis inhibitor) and chloramphenicol had poor effects on cells in glucose-sufficient conditions, combined treatment was very effective for the short term under normal glucose conditions. These results suggest the importance of controlling glucose concentration. The effect of combined treatment was also confirmed in hypoxic conditions and for patient-derived neurosphere cells. And the mechanism of cell death was ferroptosis, too. Our mitochondria-targeted treatment was effective for cells with both glucose-starved conditions and normoglycemic conditions. It is necessary to investigate its effectiveness in vivo in the future. However, chloramphenicol has already been used, and therefore, this treatment can be used for humans safely. This discovery is expected to make a major contribution to the development of treatments for glioblastomas.

Exploring Novel Therapeutic Approaches for Chronic Kidney Disease

Chronic kidney disease (CKD) is a significant global health burden, affecting millions of individuals worldwide. Despite current treatment strategies focusing on glycemic control and renin-angiotensin system blockade, these approaches merely delay the progression to end-stage renal disease (ESRD) and are associated with potential adverse effects. Recent advancements in our understanding of the complex pathophysiology of CKD have unveiled various unique processes contributing to its development, including vascular alterations, podocyte and renal epithelial cell loss, matrix deposition, inflammation, and metabolic dysregulation. This comprehensive review critically evaluates novel therapeutic approaches targeting these distinct pathways implicated in CKD pathogenesis. Strategies discussed include endothelial glycocalyx restoration, endothelin receptor antagonists, anti-apoptotic and podocyte regeneration therapies, anti-inflammatory and antioxidant agents, sodium-glucose co-transporter 2 (SGLT2) inhibitors, mitochondria-targeted therapies, anti-fibrotic agents, and interventions targeting epithelial-to-mesenchymal transition (EMT). While preclinical studies have demonstrated promising results for many of these approaches, their translation to clinical settings has been challenging due to safety concerns, lack of efficacy in trials, and the heterogeneity of CKD pathogenesis. The review highlights the importance of identifying appropriate patient populations, developing precision medicine strategies, exploring combination therapies, and leveraging novel drug delivery systems and regenerative medicine approaches to overcome current obstacles and improve therapeutic outcomes for CKD patients

Antitumor Activity and Mechanistic Insights of a Mitochondria-Targeting Cu(I) Complex.

Using copper-ionophores to translocate extracellular copper into mitochondria is a clinically validated anticancer strategy that has been identified as a new type of regulated cell death termed "cuproptosis." This study reports a mitochondria-targeting Cu(I) complex, Cu(I)Br(PPh3)3 (CBP), consisting of a cuprous ion coordinated by three triphenylphosphine moieties and a Br atom. CBP exhibited antitumor and antimetastatic efficacy in vitro and in vivo by specifically targeting mitochondria instigating mitochondrial dysfunction. The cytotoxicity of CBP could only be reversed by a copper chelator rather than inhibitors of the known cell death, indicating copper-dependent cytotoxicity. Furthermore, CBP induced the oligomerization of lipoylated proteins and the loss of Fe-S cluster proteins, consistent with characteristic features of cuproptosis. Additionally, CBP induced remarkable intracellular generation of reactive oxygen species (ROS) through a Fenton-like reaction, indicating a complex antitumor mechanism. This is a proof-of-concept study exploiting the antitumor activity and mechanism of the Cu(I)-based mitochondria-targeting therapy.

Mitochondrial Dysfunction in Chronic Obstructive Pulmonary Disease: Unraveling the Molecular Nexus.

Chronic obstructive pulmonary disease (COPD) is a prevalent and debilitating respiratory disorder characterized by persistent airflow limitation and chronic inflammation. In recent years, the role of mitochondrial dysfunction in COPD pathogenesis has emerged as a focal point of investigation. This review endeavors to unravel the molecular nexus between mitochondrial dysfunction and COPD, delving into the intricate interplay of oxidative stress, bioenergetic impairment, mitochondrial genetics, and downstream cellular consequences. Oxidative stress, a consequence of mitochondrial dysfunction, is explored as a driving force behind inflammation, exacerbating the intricate cascade of events leading to COPD progression. Bioenergetic impairment sheds light on the systemic consequences of mitochondrial dysfunction, impacting cellular functions and contributing to the overall energy imbalance observed in COPD patients. This review navigates through the genetic landscape, elucidating the role of mitochondrial DNA mutations, variations, and haplogroups in COPD susceptibility and severity. Cellular consequences, including apoptosis, autophagy, and cellular senescence, are examined, providing insights into the intricate mechanisms by which mitochondrial dysfunction influences COPD pathology. Therapeutic implications, spanning antioxidant strategies, mitochondria-targeted compounds, and lifestyle modifications, are discussed in the context of translational research. Important future directions include identifying novel biomarkers, advancing mitochondria-targeted therapies, and embracing patient-centric approaches to redefine COPD management. This abstract provides a comprehensive overview of our review, offering a roadmap for understanding and addressing the molecular nexus between mitochondrial dysfunction and COPD, with potential implications for precision medicine and improved patient outcomes.

Making a case for mitochondria in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy(HCM)is a well-known manifestation of inherited mitochondrial disease. Still, currently available gene panels do not include mitochondrial genome sequencing. Mitochondrial dysfunction plays a very important role in the pathogenesis of HCM, whether tested positive or negative by the currently available gene panels for HCM. Mitochondrial DNA variations may act as modifiers of disease manifestation in genotype-positive individuals. In genotype-negative individuals, it may be the primary driver of pathogenesis. A recent study has demonstrated that mitochondrial dysfunction is correlated with septal hypertrophy in genotype-negative HCM, which can be amenable to mitochondria-targeted therapy. It is important to consider mitochondrial genome sequencing as part of the genetic evaluation of HCM.

Beyond Quadruple Therapy and Current Therapeutic Strategies in Heart Failure with Reduced Ejection Fraction: Medical Therapies with Potential to Become Part of the Therapeutic Armamentarium.

Heart failure with reduced ejection fraction (HFrEF) is a complex clinical syndrome with significant morbidity and mortality and seems to be responsible for approximately 50% of heart failure cases and hospitalizations worldwide. First-line treatments of patients with HFrEF, according to the ESC and AHA guidelines, include β-blockers, angiotensin receptor/neprilysin inhibitors, sodium-glucose cotransporter 2 inhibitors, and mineralocorticoid receptor antagonists. This quadruple therapy should be initiated during hospital stay and uptitrated to maximum doses within 6 weeks after discharge according to large multicenter controlled trials. Quadruple therapy improves survival by approximately 8 years for a 55-year-old heart failure patient. Additional therapeutic strategies targeting other signaling pathways such as ivabradine, digoxin, and isosorbide dinitrate and hydralazine combination for African Americans, as well as adjunctive symptomatic therapies, seem to be necessary in the management of HFrEF. Although second-line medications have not achieved improvements in mortality, they seem to decrease heart failure hospitalizations. There are novel medical therapies including vericiguat, omecamtiv mecarbil, genetic and cellular therapies, and mitochondria-targeted therapies. Moreover, mitraclip for significant mitral valve regurgitation, ablation in specific atrial fibrillation cases, omecamtiv mecarbil are options under evaluation in clinical trials. Finally, the HeartMate 3 magnetically levitated centrifugal left ventricular assist device (LVAD) has extended 5-year survival for stage D HF patients who are candidates for an LVAD.

Ameliorating Mitochondrial Dysfunction for the Therapy of Parkinson's Disease.

Parkinson's disease (PD) is currently the second most incurable central neurodegenerative disease resulting from various pathogenesis. As the "energy factory" of cells, mitochondria play an extremely important role in supporting neuronal signal transmission and other physiological activities. Mitochondrial dysfunction can cause and accelerate the occurrence and progression of PD. How to effectively prevent and suppress mitochondrial disorders is a key strategy for the treatment of PD from the root. Therefore, the emerging mitochondria-targeted therapy has attracted considerable interest. Herein, the relationship between mitochondrial dysfunction and PD, the causes and results of mitochondrial dysfunction, and major strategies for ameliorating mitochondrial dysfunction to treat PD are systematically reviewed. The study also prospects the main challenges for the treatmentofPD.

In vivo mitochondria-targeted protection against uterine artery vascular dysfunction and remodelling in rodent hypoxic pregnancy.

Gestational hypoxia adversely affects uterine artery function, increasing complications. However, an effective therapy remains unidentified. Here, we show in rodent uterine arteries that hypoxic pregnancy promotes hypertrophic remodelling, increases constrictor reactivity via protein kinase C signalling, and triggers compensatory dilatation via nitric oxide-dependent mechanisms and stimulation of large conductance Ca2+ -activated K+ -channels. Maternal in vivo oral treatment with the mitochondria-targeted antioxidant MitoQ in hypoxic pregnancy normalises uterine artery reactivity and prevents vascular remodelling. From days 6-20 of gestation (term ∼22 days), female Wistar rats were randomly assigned to normoxic or hypoxic (13-14% O2 ) pregnancy±daily maternal MitoQ treatment (500 µm in drinking water). At 20 days of gestation, maternal, placental and fetal tissue was frozen to determine MitoQ uptake. The uterine arteries were harvested and, in one segment, constrictor and dilator reactivity was determined by wire myography. Another segment was fixed for unbiased stereological analysis of vessel morphology. Maternal administration of MitoQ in both normoxic and hypoxic pregnancy crossed the placenta and was present in all tissues analysed. Hypoxia increased uterine artery constrictor responses to norepinephrine, angiotensin II and the protein kinase C activator, phorbol 12,13-dibutyrate. Hypoxia enhanced dilator reactivity to sodium nitroprusside, the large conductance Ca2+ -activated K+ -channel activator NS1619 and ACh via increased nitric oxide-dependent mechanisms. Uterine arteries from hypoxic pregnancy showed increased wall thickness and MitoQ treatment in hypoxic pregnancy prevented all effects on uterine artery reactivity and remodelling. The data support mitochondria-targeted therapy against adverse changes in uterine artery structure and function in high-risk pregnancy. KEY POINTS: Dysfunction and remodelling of the uterine artery are strongly implicated in many pregnancy complications, including advanced maternal age, maternal hypertension of pregnancy, maternal obesity, gestational diabetes and pregnancy at high altitude. Such complications not only have immediate adverse effects on the growth of the fetus, but also they can also increase the risk of cardiovascular disease in the mother and offspring. Despite this, there is a significant unmet clinical need for therapeutics that treat uterine artery vascular dysfunction in adverse pregnancy. Here, we show in a rodent model of gestational hypoxia that in vivo oral treatment of the mitochondria-targeted antioxidant MitoQ protects against uterine artery vascular dysfunction and remodelling, supporting the use of mitochondria-targeted therapy against adverse changes in uterine artery structure and function in high-risk pregnancy.

REPRESSED MITOCHONDRIAL FUNCTION LIMITS CRYPT FISSIONING IN INFLAMMATORY BOWEL DISEASE

Abstract BACKGROUND Mucosal healing in inflammatory bowel disease (IBD) is a predictor of remission. Unfortunately, many IBD patients remain refractory or lose responsiveness to therapies leading to persistent mucosal ulceration. Prospective pediatric studies suggest that reduced mitochondrial gene expression associates with unfavorable clinical outcomes in ulcerative colitis (UC) and Crohn’s disease (CD). In this study, we postulate that in diverticulitis (DvC) patients, moderate-to-severe level of tissue inflammation induces fissioning of crypts with normal level of mitochondria. By comparison, in UC and CD, moderate-to-severe tissue inflammation induces lesser crypt fissioning in part due to lower level of mitochondria in crypt intestinal epithelial cells (IECs). We posit that the inability to restore epithelial mitochondrial respiration attenuates crypt fissioning in IBD compared to DvC. METHODS Surgical resections were collected from patients with colonic DvC (n=39), active Crohn’s disease (CD; n=27), ulcerative colitis (UC; n=21) and uninvolved areas of colorectal cancer patients (normal control, nc). Formalin-fixed paraffin-embedded tissues were H&amp;E-stained to allow examination of crypt architecture, branching and fissioning along with extent of inflammation scored by blinded GI-pathologist. Immunohistochemical (IHC) staining was performed for marker of mitochondrial complex-IV (MTCO1). RESULTS Histological investigations revealed higher number fissioning crypts per 100 crypts in DvC (4.778±2.9) as compared to UC (3.469±1.79) or CD (3.604±1.3) patients. This represents 37.7% and 32.6% higher crypt fissioning in DvC vs UC (**p&amp;lt;0.01) and DvC vs CD (*p&amp;lt;0.05), respectively. Alternate analysis of fissioning crypts per 100μm colonic length showed 83.9±24.8% and 22.8±9.6% more crypt fissioning in DvC compared to UC and CD, respectively. Further, IHC showed higher MTCO1 expression (area %) in DvC (14.32±3.3) compared to UC (6.6±4.85) and CD (9.25±5.9). Interestingly, all three inflammatory conditions (DvC, UC, CD) showed reduction in MTCO1 expression compared to normal control (DvC/nc: 27%; p&amp;lt;0.067, UC/nc: 71%; **p&amp;lt;0.01, CD/nc: 60.3%; **p&amp;lt;0.01), although the MTCO1 suppression in more pronounced in UC and CD. Crypt-specific MTCO1 expression revealed 2.16-fold and 1.55-fold higher MTCO1 levels in DvC compared to UC and CD, respectively. Furthermore, detailed examination of fissioning crypts in DvC, CD and UC patients revealed significantly higher expression of complex-IV protein (MTCO1) compared to non-fissioning crypts. CONCLUSION Overall, our findings suggest that lack of adequate mitochondrial function is associated with perturbed crypt fissioning in IBD patients, in contrast to DvC with comparatively higher mitochondrial complex levels. Thus, mitochondria-targeted therapy may provide an alternative treatment approach for severe chronic IBD patients.

EPITHELIAL MITOCHONDRIAL DYSFUNCTION IN CHRONIC POUCHITIS

Abstract BACKGROUND Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the surgical procedure of choice for patients with refractory ulcerative colitis (UC). However, patients with IPAA are at risk of pouch-related disorders like “pouchitis” with an incidence rate range from 20-50%. The underlying etiopathogenesis of pouchitis has been unclear, which makes management and treatment of active pouchitis difficult. Mitochondrial (Mito) dysfunction is commonly associated with pathogenesis of inflammatory bowel diseases (IBD). We posit the reduced Mito function contributes to chronic pouchitis in IPAA patients. In this study we performed comparative analysis of Mito complex levels in pouchitis patients compared to normal controls. METHODS Biopsies collected from ileal pouches +/- inflammation (n=6), and normal (n=3) and inflamed ileum (CD Ileitis; n=3 mean SES=5.2) were preserved in Allprotect® or formalin. Total RNA was extracted, cDNA synthesized and analyzed by RT-qPCR for genes specific for Mito biogenesis and complexes, cytokines and cellular antioxidant machinery. Formalin-fixed tissues were processed for IHC staining of Mito complex-I (NDUFB6) and complex-IV (MTCO1). RESULTS Transcriptomic analysis of active pouchitis tissue showed significant (**p&amp;lt;0.01) reduction of Mito biogenesis genes (PGC1α: 69.5±13.9%, TFAM: 48.7±14.5%, NRF1:48.9±17.7%) compared to normal pouch. Similar mRNA analysis in CD-ileitis showed 90.6±15.2% reduction in PGC1α gene (**p&amp;lt;0.01) and more than 62% reduction in TFAM and NRF1 genes compared normal ileum. We also observed 21.6±9.8% reduction in Mito complex I (Ndufa1, Ndufa4, Ndufb2, Ndufb6), 33.6±8.7% reduction in complex-IV (Cox5a Cox6a1, Cox5e) and 38.8±11.8% reduction in complex-V (ATP5a, ATP5b, ATP5e) in chronic pouchitis compared to normal controls. In contrast, CD-ileitis showed 59.5±10.2% reduction in Mito complexes at mRNA level compared to normal ileum. Altogether, CD-ileitis showed 26.3% and 23.8% reduction in Mito complexes and biogenesis genes, respectively, compared to pouchitis. At protein level, tissues from chronic pouchitis showed significantly reduced expression of NDUFB6 and MTCO1 compared to normal controls. However, the decreased expression of NDUFB6 and MTCO1 was more pronounced in active CD-ileitis patients. Concertedly, suppression of Mito biogenesis and complex genes correlated with upregulation of pro-inflammatory cytokines (IL1β and IL-6) and concomitant reduction of anti-oxidant genes (Sod1, Sod2, Gpx, Prdx-2,3,4,6). CONCLUSION These data indicate decreased levels of Mito complexes in pouchitis, although reductions are less prominent in active CD. We postulate that Mito dysfunction plays a role in the pathogenesis of chronic pouchitis after IPAA surgery in IBD patients. Furthermore, we posit mitochondria-targeted therapy may deliver therapeutic benefits in refractory pouchitis.

Управление старением — новая стратегия профилактики сердечно-сосудистых рисков

Aim. To analyze the potential of aging management as a new strategy for the prevention of cardiovascular diseases. Key points. The key molecular mechanisms underlying cardiovascular aging are described, including cellular senescence, oxidative stress, telomere shortening, epigenetic modifications, and chronic inflammation. The article discusses modern approaches to managing older patients with chronic coronary syndromes, including optimal medical therapy and indications for myocardial revascularization, considering age and comorbid pathology. The importance of controlling hypertension, lipid and carbohydrate metabolism disorders, geriatric syndromes, and frailty assessment is emphasized. Promising geroprotective interventions (calorie restriction, physical exercise, senolytics, mitochondria-targeted therapy) and innovative cellular and gene technologies for restoring the function of aging heart and blood vessels are considered. The necessity of a personalized and multidisciplinary approach to the prevention and treatment of cardiovascular diseases in older individuals is substantiated, taking into account biological age, comorbidity, and patient preferences. Organizational aspects of care, including cardiac rehabilitation, education, remote monitoring, and quality assessment, are considered as components of a system aimed at increasing life expectancy and quality of life in an aging society. Conclusion. Managing the aging process appears to be a promising strategy for the prevention of cardiovascular diseases. Further research should be aimed at finding safe and effective anti-aging interventions, assessing their impact on cardiovascular outcomes in clinical trials. Integration of such approaches into modern cardiology practice may help reduce morbidity and mortality from cardiovascular pathology and significantly increase the quality of life in an aging society. Keywords: cardiovascular diseases, prevention, anti-aging therapy, personalized medicine, cell technologies, cardiac rehabilitation.

The study of the protective effect of mitochondrial uncouplers during acute toxicity of the fungicide difenoconazole in different organs of mice.

Pesticides represent a serious problem for agricultural workers due to their neurotoxic effects. The aim of this study was to evaluate the ability of pharmacological oxidative phosphorylation uncouplers to reduce the effect of the difenoconazole fungicide on mitochondrial DNA (mtDNA) of various organs in mice. Injections of difenoconazole caused cognitive deficits in mice, and the protonophore 2,4-dinitrophenol (2,4-DNP) and Azur I (AzI), a demethylated metabolite of methylene blue (MB), prevented the deterioration of cognitive abilities in mice induced by difenoconazole. Difenoconazole increased the rate of reactive oxygen species (ROS) production, likely through inhibition of complex I of the mitochondrial respiratory chain. After intraperitoneal administration of difenoconazole lungs, testes and midbrain were most sensitive to the accumulation of mtDNA damage. In contrast, the cerebral cortex and hippocampus were not tolerant to the effects of difenoconazole. The protonophore 2,4-DNP reduced the rate of ROS formation and significantly reduced the amount of mtDNA damage caused by difenoconazole in the midbrain, and partially, in the lungs and testes. MB, an alternative electron carrier capable of bypassing inhibited complex I, had no effect on the effect of difenoconazole on mtDNA, while its metabolite AzI, a demethylated metabolite of MB, was able to protect the mtDNA of the midbrain and testes. Thus, mitochondria-targeted therapy is a promising approach to reduce pesticide toxicity for agricultural workers.