Activation Of Mitochondrial Biogenesis Research Articles

Network model of skeletal muscle cell signalling predicts differential responses to endurance and resistance exercise training.

Exercise-induced muscle adaptations vary based on exercise modality and intensity. We constructed a signalling network model from 87 published studies of human or rodent skeletal muscle cell responses to endurance or resistance exercise in vivo or simulated exercise in vitro. The network comprises 259 signalling interactions between 120 nodes, representing eight membrane receptors and eight canonical signalling pathways regulating 14 transcriptional regulators, 28 target genes and 12 exercise-induced phenotypes. Using this network, we formulated a logic-based ordinary differential equation model predicting time-dependent molecular and phenotypic alterations following acute endurance and resistance exercises. Compared with nine independent studies, the model accurately predicted 18/21 (85%) acute responses to resistance exercise and 12/16 (75%) acute responses to endurance exercise. Detailed sensitivity analysis of differential phenotypic responses to resistance and endurance training showed that, in the model, exercise regulates cell growth and protein synthesis primarily by signalling via mechanistic target of rapamycin, which is activated by Akt and inhibited in endurance exercise by AMP-activated protein kinase. Endurance exercise preferentially activates inflammation via reactive oxygen species and nuclear factor κB signalling. Furthermore, the expected preferential activation of mitochondrial biogenesis by endurance exercise was counterbalanced in the model by protein kinase C in response to resistance training. This model provides a new tool for investigating cross-talk between skeletal muscle signalling pathways activated by endurance and resistance exercise, and the mechanisms of interactions such as the interference effects of endurance training on resistance exercise outcomes.

Lycopene as a Therapeutic Agent against Aflatoxin B1-Related Toxicity: Mechanistic Insights and Future Directions.

Aflatoxin (AFT) contamination poses a significant global public health and safety concern, prompting widespread apprehension. Of the various AFTs, aflatoxin B1 (AFB1) stands out for its pronounced toxicity and its association with a spectrum of chronic ailments, including cardiovascular disease, neurodegenerative disorders, and cancer. Lycopene, a lipid-soluble natural carotenoid, has emerged as a potential mitigator of the deleterious effects induced by AFB1 exposure, spanning cardiac injury, hepatotoxicity, nephrotoxicity, intestinal damage, and reproductive impairment. This protective mechanism operates by reducing oxidative stress, inflammation, and lipid peroxidation, and activating the mitochondrial apoptotic pathway, facilitating the activation of mitochondrial biogenesis, the endogenous antioxidant system, and the nuclear factor erythroid 2-related factor 2 (Nrf2)/kelch-like ECH-associated protein 1 (KEAP1) and peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1) pathways, as well as regulating the activities of cytochrome P450 (CYP450) enzymes. This review provides an overview of the protective effects of lycopene against AFB1 exposure-induced toxicity and the underlying molecular mechanisms. Furthermore, it explores the safety profile and potential clinical applications of lycopene. The present review underscores lycopene's potential as a promising detoxification agent against AFB1 exposure, with the intent to stimulate further research and practical utilization in this domain.

Protein Interaction Assessing Mitochondrial Biogenesis as a Next Generation Biomarker in Sepsis: A Prospective Cohort Study

BackgroundMetabolic derangements in sepsis stem from mitochondrial injury and contribute to organ dysfunction and mortality. Thus, repair of mitochondrial damage seems pivotal for recovery and determining clinical outcome in sepsis. However, reliable biomarkers assessing mitochondrial repair noninvasively in peripheral blood are currently lacking. Research QuestionAre different gene transcripts related to mitochondrial repair (i.e., biogenesis, fusion, fission, mitophagy) and the protein interaction assessing mitochondrial biogenesis, both measured in peripheral blood, associated with disease severity and clinical outcome? Study Design and MethodsHealthy controls (n=22), uninfected critically ill control patients (n=13), and 75 sepsis patients were included in this prospective multicentric observational study. Gene products of mitochondrial quality control and mitochondrial DNA were measured on day 1 and 4 in peripheral blood mononuclear cells. In addition, we assessed in the same samples the mitochondrial protein interaction of TFAM-TFB2M using a proximity ligation assay. Septic patients were stratified in the outcome-related subgroups “ICU-free within 1 week” (n=16), “Not ICU-free within 1 week” (n=36), and “30-day non-survivors” (n=23). ResultsTranscript levels of the assessed mRNA markers of septic patients were not associated with disease severity nor did they predict clinical outcome. Strikingly, the mitochondrial protein interaction of TFAM-TFB2M on day 4 (p<0.05) as well as the difference between day 1 and 4 (p<0.001) allowed stratification in the three clinical outcome subgroups. In addition, a decline in TFAM-TFB2M protein interactions between day 1 and day 4 was an independent predicator for 30-day mortality (aHR: 8.34; 95% CI: 2.73 to 25.45, p<0.001). InterpretationSepsis patients with an early activation of mitochondrial biogenesis were more likely to be ICU-free within 1 week. A mitochondrial and clinical recovery can be assessed via the protein interaction of TFAM-TFB2M in peripheral blood. Thus, mitochondrial protein interactions targeting mitochondrial biogenesis provide a promising dimension of novel biomarkers assessing mitochondrial dysfunction in sepsis.

Mitophagy regulates mitochondrial number following pharmacological induction of mitochondrial biogenesis in renal proximal tubule cells.

Background: Mitochondrial biogenesis (MB) induction through the activation of the 5-Hydroxytriptamine (5-HT) 1F receptor (HTR1F) is a promising mechanism for the treatment of diseases characterized by mitochondrial dysfunction, such as acute kidney injury (AKI). While several studies report pharmacological activation of MB in the proximal tubule, it is unclear how the proximal tubule regulates itself once the pharmacological activation is removed. Mitophagy is the process of selective mitochondria degradation. We hypothesize that mitophagy decreases mitochondrial number after pharmacological stimulation and restore mitochondrial homeostasis. Methods: Renal proximal tubules were treated at time 0hr with LY344864 or vehicle for 24h and then removed. LY344864, a selective HTR1F agonist, induces MB in renal proximal tubules as previously reported (Gibbs et al., Am J Physiol Renal Physiol, 2018, 314(2), F260-F268). Vehicle and pharmacological reagents were added at the 24h time point. Electron microscopy was used to assess mitochondrial morphology, number, and autolysosomes. Seahorse Bioscience XF-96 extracellular flux analyzer was used to measure maximal mitochondrial oxygen consumption rates (FCCP-OCR), a functional marker of MB. Results: LY344864 treatment increased FCCP-OCR, phosphorylation of protein kinase B (AKT), peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC-1α), and mitochondrial number after 24h. These endpoints decreased to baseline 24h after LY344864 removal. Treatment with ROC-325, an autophagy inhibitor, increased Sequestosome-1 (SQSTM1/P62) and microtubule-associated protein-1 light chain 3 (LC3B) after 24h of treatment. Also, ROC-325 treatment sustained the elevated mitochondrial number after LY344864 pre-treatment and removal. Conclusion: These data revealed that inhibition of autophagy extends elevated mitochondrial number and function by preventing the lysosomal degradation of mitochondria after the removal of LY344864.

GW501516 (Cardarine): Pharmacological and Clinical Effects

GW501516/Cardarine is a nuclear hormone that activates the PPARδ genes involved in cell differentiation and exerts a primary regulation in maintaining health conditions and preventing diseases. PPARδ activation stimulates the mitochondrial function in various tissues improving lipid metabolism and energy homeostasis. PPARδ receptors are expressed mainly in active metabolic tissues such as skeletal muscles, the heart, the liver, and neurons. PPARδ activation increases fatty acid oxidation, saving glycogen stores, so they find indications for the treatment of metabolic diseases, especially dyslipidemia and type-2 diabetes mellitus (T2DM), and hypertriglyceridemia. The pancreatic β-cell function is improved. In the heart, PPARδ improves cardiomyocytes function and reduces fibrosis. In the liver, it reduces the fat deposit, suppressing inflammation. Cardarine seems to be effective in preventing β-amyloid deposition and Alzheimer’s disease. In the skeletal muscles, cardarine induces a strong activation of mitochondrial biogenesis, increasing oxidative muscle capacity and endurance exercise capacity, and for this reason, it was included in the list of doping agents by WADA. However, some controversies on cancer risk stimulation exist. This review aims to evaluate the clinical benefits and side effects of GW501516/ cardarine.

Enhanced mitochondrial biogenesis promotes neuroprotection in human pluripotent stem cell derived retinal ganglion cells

Mitochondrial dysfunctions are widely afflicted in central nervous system (CNS) disorders with minimal understanding on how to improve mitochondrial homeostasis to promote neuroprotection. Here we have used human stem cell differentiated retinal ganglion cells (hRGCs) of the CNS, which are highly sensitive towards mitochondrial dysfunctions due to their unique structure and function, to identify mechanisms for improving mitochondrial quality control (MQC). We show that hRGCs are efficient in maintaining mitochondrial homeostasis through rapid degradation and biogenesis of mitochondria under acute damage. Using a glaucomatous Optineurin mutant (E50K) stem cell line, we show that at basal level mutant hRGCs possess less mitochondrial mass and suffer mitochondrial swelling due to excess ATP production load. Activation of mitochondrial biogenesis through pharmacological inhibition of the Tank binding kinase 1 (TBK1) restores energy homeostasis, mitigates mitochondrial swelling with neuroprotection against acute mitochondrial damage for glaucomatous E50K hRGCs, revealing a novel neuroprotection mechanism.

Naringin protects mice from D-galactose-induced lung aging and mitochondrial dysfunction: Implication of SIRT1 pathways

AimAging is the leading risk factor for diminishing lung function, as well as injury and lung disorder. The target of our research was to examine the potential protective effect of naringin and the possible role of SIRT1 in mice with D-galactose-induced lung aging, by evaluating its effects on antioxidant systems, mitochondrial biogenesis, autophagy, and apoptosis, by referring to the potential involvement of Nrf2/NQO1, LKB1/AMPK/PGC-1α, FOXO1, and P53/caspase-3 signaling. Material and methodsThe mice were randomly sorted into 5 groups (10 each): 1st: normal group received subcutaneous normal saline and intragastric distilled water, 2nd: naringin 300 mg/kg orally, 3rd: D-galactose (200 mg/kg/day) was administered subcutaneously into mice for eight weeks, to accelerate aging, 4th & 5th: oral naringin (150, 300 mg/kg) was given daily concurrently with D-galactose injection for 8 weeks. Key findingIn silico investigation revealed that naringin substantially stimulates the SIRT1 and AMPK molecules. At the molecular level, our findings indicated that treatment with naringin stimulated the mitochondrial biogenesis pathway through regulation of the LKB1/AMPK/PGC-1α signals and upregulated FOXO1-mediated autophagy. Furthermore, naringin exhibited antioxidant properties by activating the Nrf2/NQO1 pathway and inhibiting MDA and AGEs levels. In addition, Naringin ameliorated alveolar spaces destruction and bronchial wall thickening, as well as alleviated P53/caspase-3 apoptosis signaling. SignificanceNaringin exerts protective effects against D-galactose-induced lung aging and enhances longevity by activating SIRT1. SIRT1 regulates various aging-related molecular pathways via restoring pro-oxidant/antioxidant homeostasis, activation of mitochondrial biogenesis, modulating of autophagy and inhibition of apoptosis.

Role of mitochondria in brain functions and related disorders

Mitochondria are important organelles for high energy synthesis, reactive oxygen species balancing, antiapoptotic molecule production, membrane stability, intracellular calcium buffering, neuroplasticity and neurotransmission. Dysfunction in mitochondria is considered to be involved in the pathophysiology of mental problems. It has been observed that several drug types used to treat brain illnesses can harm mitochondria by altering the oxidative phosphorylation system and the gene expression of mitochondria-related proteins. In some studies, it has been observed that mitochondrial biogenesis shows a therapeutic effect in the management of mitochondrial disorders. Many therapeutic compounds are effective in the activation of mitochondrial biogenesis. The comorbidity of mental problems observed in those with mitochondrial dysfunction and the change in the efficacy of the cellular respiratory system have attracted researchers to understand the pathways and possible therapeutic strategies in neurological disorders. This article has attempted to understand the impact of mitochondrial function and mitochondrial dysfunction in the pathogenesis of brain disorders to develop potential therapeutic drugs.

The Pro-Inflammatory Deletion Allele of the NF-κB1 Polymorphism Is Characterized by a Depletion of Subunit p50 in Sepsis.

The functionally important NF-κB1 promoter polymorphism (−94ins/delATTG) significantly shapes inflammation and impacts the outcome of sepsis. However, exploratory studies elucidating the molecular link of this genotype-dependent pattern are lacking. Accordingly, we analyzed lipopolysaccharide-stimulated peripheral blood mononuclear cells from both healthy volunteers (n = 20) and septic patients (n = 10). All individuals were genotyped for the −94ins/delATTG NF-κB1 promoter polymorphism. We found a diminished nuclear activity of the NF-κB subunit p50 in ID/DD genotypes after 48 h of lipopolysaccharide stimulation compared to II genotypes (p = 0.025). This was associated with higher TNF-α (p = 0.005) and interleukin 6 concentrations (p = 0.014) and an increased production of mitochondrial radical oxygen species in ID/DD genotypes (p = 0.001). Although ID/DD genotypes showed enhanced activation of mitochondrial biogenesis, they still had a significantly diminished cellular ATP content (p = 0.046) and lower mtDNA copy numbers (p = 0.010) compared to II genotypes. Strikingly, these findings were mirrored in peripheral blood mononuclear cells taken from septic patients. Our results emphasize the crucial aspect of considering NF-κB subunits in sepsis. We showed here that the deletion allele of the NF-κB1 (−94ins/delATTG) polymorphism was associated with the lower nuclear activity of subunit p50, which, in turn, was associated with aggravated inflammation and mitochondrial dysfunction.

Multi-Ingredient Supplement Supports Mitochondrial Health through Interleukin-15 Signaling in Older Adult Human Dermal Fibroblasts

The macroscopic and microscopic deterioration of human skin with age is, in part, attributed to a functional decline in mitochondrial health. We previously demonstrated that exercise attenuated age-associated changes within the skin through enhanced mitochondrial health via IL-15 signaling, an exercise-induced cytokine whose presence increases in circulation following physical activity. The purpose of this investigation was to determine if these mitochondrial-enhancing effects could be mimicked with the provision of a novel multi-ingredient supplement (MIS). Cultured human fibroblasts isolated from older, sedentary women were treated with control media (CON) or CON supplemented with the following active ingredients to create the MIS: coenzyme Q10, alpha lipoic acid, resveratrol, curcumin, zinc, lutein, astaxanthin, copper, biotin, and vitamins C, D, and E. Outcomes were determined following 24 or 72 h of treatment. MIS provision to dermal fibroblasts significantly increased the mRNA abundance of mitochondrial biogenesis activators and downstream IL-15 signaling pathways, and proteins for oxidative phosphorylation subunits and antioxidant defenses. These findings were co-temporal with lower cellular senescence and cytotoxicity following MIS treatment. In summary, MIS supplementation led to exercise-mimetic effects on human dermal fibroblasts and their mitochondria by reproducing the molecular and biochemical effects downstream of IL-15 activation.

Nrf2 Activation Attenuates Chronic Constriction Injury-Induced Neuropathic Pain via Induction of PGC-1α-Mediated Mitochondrial Biogenesis in the Spinal Cord.

Background Neuropathic pain is a debilitating disease with few effective treatments. Emerging evidence indicates the involvement of mitochondrial dysfunction and oxidative stress in neuropathic pain. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a potent regulator of the antioxidant response system. In this study, we investigated whether RTA-408 (RTA, a novel synthetic triterpenoid under clinical investigation) could activate Nrf2 and promote mitochondrial biogenesis (MB) to reverse neuropathic pain and the underlying mechanisms. Methods Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve. Pain behaviors were measured via the von Frey test and Hargreaves plantar test. The L4-6 spinal cord was collected to examine the activation of Nrf2 and MB. Results RTA-408 treatment significantly reversed mechanical allodynia and thermal hyperalgesia in CCI mice in a dose-dependent manner. Furthermore, RTA-408 increased the activity of Nrf2 and significantly restored MB that was impaired in CCI mice in an Nrf2-dependent manner. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) is the key regulator of MB. We found that the PGC-1α activator also induced a potent analgesic effect in CCI mice. Moreover, the antinociceptive effect of RTA-408 was reversed by the preinjection of the PGC-1α inhibitor. Conclusions Nrf2 activation attenuates chronic constriction injury-induced neuropathic pain via induction of PGC-1α-mediated mitochondrial biogenesis in the spinal cord. Our results indicate that Nrf2 may be a potential therapeutic strategy to ameliorate neuropathic pain and many other disorders with oxidative stress and mitochondrial dysfunction.

Resveratrol enhanced mitochondrial recovery from cryopreservation-induced damages in oocytes and embryos.

BackgroundMitochondria play a crucial role in nuclear maturation, fertilization, and subsequent embryo development. Cryopreservation is an important assisted reproductive technology that is used worldwide for humans and domestic animals. Although mitochondrial quantity and quality are decisive factors for successful development of oocytes and embryos, cryopreservation induces mitochondrial dysfunction. Upon thawing, the damaged mitochondria are removed, and de novo synthesis occurs to restore the function of mitochondria. Resveratrol, 3,5,4′‐trihydroxystilbene, is a polyphenolic antioxidant that has versatile target proteins, among which sirtuin‐1 (SIRT1) is a key regulator of in mitochondrial biogenesis and degradation.MethodsThe present study is a literature review focusing on experiments involving the hypothesis that the activation of mitochondrial biogenesis and degradation following cryopreservation and warming by resveratrol may help mitochondrial recovery and improve oocyte and embryo development.Main findings and conclusionResveratrol improves oocyte maturation and development and upregulates mitochondrial biogenesis and degradation. When vitrified‐warmed embryos are treated with resveratrol, it helps in mitochondrial regulation and recovery of embryos from cryopreservation‐induced damage.ConclusionResveratrol treatment is a possible countermeasure against cryopreservation‐induced mitochondrial damage.

Abnormalities in Mitochondrial DNA Copy Number Have Pathogenetic and Prognostic Implications in Multiple Myeloma

Mitochondria are bioenergetic and biosynthetic organelles which control crucial biological pathways such as cell growth, proliferation and apoptosis among others. Over the last two decades, many studies have examined the role of mitochondrial DNA (mtDNA) alterations in carcinogenesis, via inactivating genetic mutations or dysregulation of the mtDNA copy number in the cell. However, the status of the mtDNA copy number and its implication in the pathogenesis of Multiple Myeloma (MM) remains unknown. Here, we have analyzed the mtDNA copy number in asymptomatic and symptomatic stages of MM and evaluated its clinical impact.We have estimated the mtDNA copy number in purified plasma cells from 139 patients across different stages of the disease (4 healthy donor, 19 MGUS, 14 Smoldering MM (SMM), 78 newly diagnosed MM (ndMM) and 24 relapse (rMM). The mtDNA copy number quantification was performed by RT-PCR using 2 Taqman probes which targeted the mitochondrial gene MT-RNR1 and the nuclear gene RPPH1. We have also used whole-genome or whole-exome sequencing data to examine changes in mtDNA copy number in newly-diagnosed or relapsed MM (n=64 samples) including paired sample from SMM patients progressing to ndMM (n=10). FastMitocalc and Samtools were used to extract reads aligning to mitochondrial genome from bam files and calculate de mtDNA copy number by comparing to the number of reads aligning to nuclear genome. Differential gene expression analysis was done by using canEvolve.org ocogenomics web portal (Multiple Myeloma, GSE6477 study).We observed a significant increase in the average mtDNA copy number in myeloma cells compared to healthy plasma cells (39 vs 228 copies; p-value = 0.02). Plasma cells from MGUS cells showed lower mtDNA content than more advanced stages of the disease (129 vs 242 mtDNA copies). Interestingly, amongst 10 paired samples from SMM progressing to MM an increase in the mtDNA copy number was observed in 8 of the 10 patients, being more evident when the time to progression was longer. Additionally, we also observed an increase in the mitochondrial content in 17 of the 21 patient samples examined pre and post relapse, including those patients with three consecutive relapsed samples available. We have evaluated the impact on survival of the mtDNA copy number in 69 newly diagnosed patients and we have found that patients with greater than 400 mtDNA copy number had significantly shorter progression free survival compared to the rest (p-value = 0.024). The differential expression analysis of plasma cells from MGUS, SMM, ndMM and rMM patients compared to normal plasma cells confirmed an overexpression of the mitochondrial biogenesis regulators (TFAM, TUFM, MYC and HNRNPK).We describe for the first time that mtDNA copy number increase across different stages of MM. Our data provides evidence that the malignant transformation of the myeloma cells from asymptomatic stages implies activation of mitochondrial biogenesis resulting in increased mtDNA levels. Functional experiments are ongoing to confirm the metabolic activation of myeloma cells over the time. These results highlight mitochondria as an important component of pathogenesis and progression of MM and as a potential target for therapy. DisclosuresNo relevant conflicts of interest to declare.

Pathogenetic and Prognostic Implications of Increased Mitochondrial Content in Multiple Myeloma.

Simple SummaryMonoclonal gammopathies comprise a spectrum of disorders defined by the clonal proliferation of plasma cells and include monoclonal gammopathy of undetermined significance (MGUS), smoldering MM (SMM) and multiple myeloma (MM), which can also evolve from MGUS and SMM. We aimed to analyze the impact of mitochondrial DNA copy number (mtDNACN) and also SNVs and INDELs in frequently mutated mitochondrial-related genes on the disease course of monoclonal gammopathies and MM. We confirmed the increased levels of mtDNA in SMM and MM, their gain as the gammopathy progresses and the similarities in the mitochondrial hallmarks between rapidly-progressing SMM and MM. Our data suggest that mitochondria participate in the malignant transformation of monoclonal gammopathies and contribute to disease progression. Our findings support the clinical importance of mtDNACN evaluation and monitoring to guide clinical decision making in patients with SMM.Many studies over the last 20 years have investigated the role of mitochondrial DNA (mtDNA) alterations in carcinogenesis. However, the status of the mtDNACN in MM and its implication in the pathogenesis of the disease remains unclear. We examined changes in plasma cell mtDNACN across different stages of MM by applying RT-PCR and high-throughput sequencing analysis. We observed a significant increase in the average mtDNACN in myeloma cells compared with healthy plasma cells (157 vs. 40 copies; p = 0.02). We also found an increase in mtDNACN in SMM and newly diagnosed MM (NDMM) paired samples and in consecutive relapses in the same patient. Survival analysis revealed the negative impact of a high mtDNACN in progression-free survival in NDMM (p = 0.005). Additionally, we confirmed the higher expression of mitochondrial biogenesis regulator genes in myeloma cells than in healthy plasma cells and we detected single nucleotide variants in several genes involved in mtDNA replication. Finally, we found that there was molecular similarity between “rapidly-progressing SMM” and MM regarding mtDNACN. Our data provide evidence that malignant transformation of myeloma cells involves the activation of mitochondrial biogenesis, resulting in increased mtDNA levels, and highlights vulnerabilities and potential therapeutic targets in the treatment of MM. Accordingly, mtDNACN tracking might guide clinical decision-making and management of complex entities such as high-risk SMM.

Salidroside protects cardiac function in mice with diabetic cardiomyopathy via activation of mitochondrial biogenesis and SIRT3.

To investigate the effects and the underlying mechanisms of salidroside on diabetic cardiomyopathy, diabetes was induced in mice by a long-term high-fat diet and a low-dose injection of streptozocin. Measurements of cardiac function, biochemical analysis, and histopathological examinations were conducted to evaluate the therapeutic effects of salidroside. In this study, we found that diabetic mice exhibited decreased cardiac systolic function and impaired mitochondrial ultrastructure. Pre-treatment with salidroside protected mice against myocardial dysfunction, reduced blood glucose, improved insulin resistance, and induced mitochondrial biogenesis. Neonatal rat cardiomyocytes were cultured to explore the mechanisms of salidroside in vitro. Salidroside alleviated decreased expression of peroxisome proliferator-activated receptor-γ coactivator 1-alpha (PGC-1α), mitochondrial transcription factor A (TFAM) via phosphorylation of 5' AMP-activated protein kinase (AMPK), which may be associated with mitochondrial biogenesis. Salidroside also increased sirtuin-3 (SIRT3) expression in cardiomyocytes. Furthermore, salidroside promoted the translocation of SIRT3 from cytoplasm to mitochondria and increased the deacetylation of mitochondrial proteins such as manganese-dependent superoxide dismutase (MnSOD). In Conclusion, salidroside not only improved diabetes, but also ameliorated diabetic cardiomyopathy, which was at least partly associated with the activation of mitochondrial SIRT3, AMPK/Akt, and PGC-1α/TFAM and subsequent improving mitochondrial function.

Atorvastatin reverses high cholesterol-induced cardiac remodelling and regulates mitochondrial quality-control in a cholesterol-independent manner: An experimental study.

Mitochondria are key regulators of cell fate, maintaining self-stability by a fine-tuned quality-control network including mitophagy, biogenesis, fission and fusion processes. Myocardial mitochondria can be impaired by hypercholesterolemia. Statins, such as atorvastatin, are considered thecornerstonein the management of hypercholesterolaemia primarily due to their marked cholesterol-lowering ability. The direct effect of atorvastatin on myocardial mitochondria remains unclear. We aimed to explore whether atorvastatin could attenuate myocardial mitochondrial defects induced by high cholesterol, and whether cycloastragenol, a potent telomerase activator, could be used as a potential complementary bioactive compound for obesity and hypercholesterolaemia treatment. We found that atorvastatin at a low dose (3mg/kg) did not reduce elevated serum cholesterol, but reversed cardiac remodelling and dysfunction in C57BL/6J mice fed with high-fat diet (HFD). Atorvastatin reversed the upregulated mitophagy, mitochondrial fission and fusion, accompanied by mitochondrial biogenesis activation in HFD-fed mice hearts. Mitochondrial structural impairments were attenuated by atorvastatin in HFD-fed mice and oxidized low-density lipoprotein (ox-LDL) exposed HL-1 cardiomyocytes. The depolarized mitochondrial membrane potential and increased mitochondrial oxygen consumption rates in ox-LDL exposed HL-1 cells were recovered by atorvastatin. Furthermore, atorvastatin co-treated with cycloastragenol had better effects on reducing body weight, improving cardiac remodelling and dysfunction, and protecting mitochondria in high cholesterol. Conclusively, low-dose atorvastatin exhibited a cholesterol-independent cardioprotective effect through improving the mitochondrial quality-control network and repairing mitochondrial ultrastructure in high cholesterol. Atorvastatin plus cycloastragenol supplement therapy has a better effect on treating obesity and hypercholesterolaemia.

Optogenetic stimulation of entorhinal cortex reveals the implication of insulin signaling in adult rat’s hippocampal neurogenesis

Adult neurogenesis in the hippocampal dentate gyrus plays a critical role in learning and memory. Projections originating from entorhinal cortex, known as the perforant pathway, provide the main input to the dentate gyrus and promote neurogenesis. However, neuromodulators and molecular changes mediating neurogenic effects of this pathway are not yet fully understood. Here, by means of an optogenetic approach, we investigated neurogenesis and synaptic plasticity in the hippocampus of adult rats induced by stimulation of the perforant pathway. The lentiviruses carrying hChR2 (H134R)-mCherry gene under the control of the CaMKII promoter were injected into the medial entorhinal cortex region of adult rats. After 21 days, the entorhinal cortex region was exposed to the blue laser (473 nm) for five consecutive days (30 min/day). The expression of synaptic plasticity and neurogenesis markers in the hippocampus were evaluated using molecular and histological approaches. In parallel, the changes in the gene expression of insulin and its signaling pathway, trophic factors, and components of mitochondrial biogenesis were assessed. Our results showed that optogenetic stimulation of the entorhinal cortex promotes hippocampal neurogenesis and synaptic plasticity concomitant with the increased levels of insulin mRNA and its signaling markers, neurotrophic factors, and activation of mitochondrial biogenesis. These findings suggest that effects of perforant pathway stimulation on the hippocampus, at least in part, are mediated by insulin increase in the dentate gyrus and subsequently activation of its downstream signaling pathway.

Mildronate protects heart mtDNA from oxidative stress toxicity induced by exhaustive physical exercise

Exhaustive physical exercises are potentially dangerous for human's physical health and may lead to chronic heart disease. Therefore, individuals involved in such activity require effective and safe cardioprotectors. The goal of this research was to study Mildronate (a cardioprotective drug) effect on the level of oxidative stress markers in hearts of mice under conditions of exhausting physical exercise, such as forced swimming for 1 h per day for 7 days. Forced swimming lead to mtDNA damage accumulation, increase in diene conjugates level and loss of reduced glutathione despite an increase in antioxidant genes expression and activation of mitochondrial biogenesis. Mildronate treatment reduced oxidative stress, probably due to the inhibition of fatty acids transport to mitochondria and an increase in the intensity of glucose oxidation, which in part confirms by increase in glucose transporter expression. Thus, we can assume that Mildronate is an effective cardioprotector in exhaustive physical exercises.

BGP-15 Protects against Heart Failure by Enhanced Mitochondrial Biogenesis and Decreased Fibrotic Remodelling in Spontaneously Hypertensive Rats.

Heart failure (HF) is a complex clinical syndrome with poor clinical outcomes despite the growing number of therapeutic approaches. It is characterized by interstitial fibrosis, cardiomyocyte hypertrophy, activation of various intracellular signalling pathways, and damage of the mitochondrial network. Mitochondria are responsible for supplying the energy demand of cardiomyocytes; therefore, the damage of the mitochondrial network causes cellular dysfunction and finally leads to cell death. BGP-15, a hydroxylamine derivative, is an insulin-sensitizer molecule and has a wide range of cytoprotective effects in animal as well as in human studies. Our recent work was aimed at examining the effects of BGP-15 in a chronic hypertension-induced heart failure model. 15-month-old male SHRs were used in our experiment. The SHR-Baseline group represented the starting point (n = 7). Animals received BGP-15 (SHR-B, n = 7) or placebo (SHR-C, n = 7) for 18 weeks. WKY rats were used as age-matched normotensive controls (n = 7). The heart function was monitored by echocardiography. Histological preparations were made from cardiac tissue. The levels of signalling proteins were determined by Western blot. At the end of the study, systolic and diastolic cardiac function was preserved in the BGP-treated animals. BGP-15 decreased the interstitial collagen deposition via decreasing the activity of TGFβ/Smad signalling factors and prevented the cardiomyocyte hypertrophy in hypertensive animals. BGP-15 enhanced the prosurvival signalling pathways (Akt/Gsk3β). The treatment increased the activity of MKP1 and decreased the activity of p38 and JNK signalling routes. The mitochondrial mass of cardiomyocytes was also increased in BGP-15-treated SHR animals due to the activation of mitochondrial biogenesis. The mitigation of remodelling processes and the preserved systolic cardiac function in hypertension-induced heart failure can be a result—at least partly—of the enhanced mitochondrial biogenesis caused by BGP-15.

Penicilliumin B Protects against Cisplatin-Induced Renal Tubular Cell Apoptosis through Activation of AMPK-Induced Autophagy and Mitochondrial Biogenesis

Introduction: Acute kidney injury (AKI) is at a high prevalence in hospitalized patients, especially in those receiving chemotherapy. Cisplatin is the most widely used chemotherapy drug; however, with its side effects that include nephrotoxicity, it also exhibits a risk of inducing AKI. Importantly, recent studies have shown that autophagy plays a protective role in cisplatin-induced AKI. However, therapeutic strategies and candidate drugs for inducing activation of autophagy remain limited. Methods: In the present study, we adopted a novel candidate drug from a deep sea-derived Penicillium strain, penicilliumin B, to testify its protective role in cisplatin-induced renal tubular cell injury. Results: Penicilliumin B exhibited protection against cisplatin-induced apoptosis in cultured renal tubular epithelial cells and in cisplatin-treated mice. Moreover, penicilliumin B maintained normal mitochondrial morphology and inhibited the production of mitochondrial reactive oxygen species. Further studies demonstrated that penicilliumin B enhanced autophagic flux, promoted the activation of multiple autophagy-related proteins, such as mTOR, Beclin-1, ATG5, PINK1, and LC3B, and induced the degradation of p62. Interestingly, we also found penicilliumin B triggered phosphorylation of adenosine 5‘-monophosphate-activated protein kinase (AMPK), which is an upstream inducer of nearly all autophagy pathways and also an activator of mitochondrial biogenesis. These results suggest that AMPK may represent an activated site of penicilliumin B. Consistently, compound C, an AMPK inhibitor, significantly blocked the protective effects of penicilliumin B on mitochondria and apoptotic inhibition. Conclusion: Taken together, our findings indicate that penicilliumin B represents a novel AMPK activator that may provide protection against renal tubular cell apoptosis through activation of AMPK-induced autophagy and mitochondrial biogenesis.