Mitochondrial metabolism blockade nanoadjuvant reversed immune-resistance microenvironment to sensitize albumin-bound paclitaxel-based chemo-immunotherapy

Currently, the efficacy of albumin-bound paclitaxel (PTX@Alb) is still limited due to theimpaired PTX@Alb accumulation in tumors partly mediated by the dense collagen distribution. Meanwhile,acquired immune resistance always occurs due to the enhanced programmed cell death-ligand 1(PD-L1) expression after PTX@Alb treatment, which then leads to immune tolerance. To fill these gaps,we newly revealed that tamoxifen (TAM), a clinically widely used adjuvant therapy for breast cancer withmitochondrial metabolism blockade capacity, could also be used as a novel effective PD-L1 and TGF-bdual-inhibitor via inducing the phosphorylation of adenosine 5ʹ-monophosphate-activated protein kinase(AMPK) protein. Following this, to obtain a more significant effect, TPP-TAM was prepared by conjugatingmitochondria-targeted triphenylphosphine (TPP) with TAM, which then further self-assembledwith albumin (Alb) to form TPP-TAM@Alb nanoparticles. By doing this, TPP-TAM@Alb nanoparticleseffectively decreased the expression of collagen in vitro, which then led to the enhanced accumulation ofPTX@Alb in 4T1 tumors. Besides, TPP-TAM@Alb also effectively decreased the expression of PD-L1 and TGF-b in tumors to better sensitize PTX@Alb-mediated chemo-immunotherapy by enhancing T cellinfiltration. All in all, we newly put forward a novel mitochondrial metabolism blockade strategy toinhibit PTX@Alb-resistant tumors, further supporting its better clinical application。

Latest assessment methods for mitochondrial homeostasis in cognitive diseases

Mitochondria play an essential role in neural function,such as supporting normal energy metabolism,regulating reactive oxygen species,buffering physiological calcium loads,and maintaining the balance of morphology,subcellular distribution,and overall health through mitochondrial dynamics.Given the recent technological advances in the assessment of mitochondrial structure and functions,mitochondrial dysfunction has been regarded as the early and key pathophysiological mechanism of cognitive disorders such as Alzheimer’s disease,Parkinson’s disease,Huntington’s disease,mild cognitive impairment,and postoperative cognitive dysfunction.This review will focus on the recent advances in mitochondrial medicine and research methodology in the field of cognitive sciences,from the perspectives of energy metabolism,oxidative stress,calcium homeostasis,and mitochondrial dynamics(including fission-fusion,transport,and mitophagy).

Coordinated regulation of BACH1 and mitochondrial metabolism through tumor-targeted self-assembled nanoparticles for effective triple negative breast cancer combination therapy

The poor prognosis of triple negative breast cancer(TNBC)results from a lack of approved targeted therapies coupled with aggressive proliferation and metastasis,which is associated with high recurrence and short overall survival.Here we developed a strategy by employing tumor-targeted selfassembled nanoparticles to coordinately regulate BACH1(BTB domain and CNC homology 1)and mitochondrial metabolism.The BACH1 inhibitor hemin and mitochondria function inhibitor berberine derivative(BD)were used to prepare nanoparticles(BH NPs)followed by the modification of chondroitin sulfate(CS)on the surface of BH NPs to achieve tumor targeting(CS/BH NPs).CS/BH NPs were found to be able to inhibit tumor migration and invasion by significantly decreasing the amounts of tumor cell metabolites,glycolysis and metastasis-associated proteins,which were related to the inhibition of BACH1 function.Meanwhile,decreased mitochondrial membrane potential,activated caspase 3/9 and increased ROS production demonstrated coordinated regulation of BACH1 and mitochondrial metabolism.In a xenograft mice model of breast cancer,CS/BH NPs significantly inhibited tumor growth and metastasis due to the synergetic effect of hemin and BD without showing obvious toxicities for major organs.In sum,the results of efficacy and safety experiments suggest potential clinical significance of the prepared self-assembled CS/BH nanoparticles for the treatment of TNBC.

Mitochondrial energy metabolism in diabetic cardiomyopathy:Physiological adaption,pathogenesis,and therapeutic targets

Diabetic cardiomyopathy is defined as abnormal structure and function of the heart in the setting of diabetes,which could eventually develop heart failure and leads to the death of the patients.Although blood glucose control and medications to heart failure show beneficial effects on this disease,there is currently no specific treatment for diabetic cardiomyopathy.Over the past few decades,the pathophysiology of diabetic cardiomyopathy has been extensively studied,and an increasing number of studies pinpoint that impaired mitochondrial energy metabolism is a key mediator as well as a therapeutic target.In this review,we summarize the latest research in the field of diabetic cardiomyopathy,focusing on mitochondrial damage and adaptation,altered energy substrates,and potential therapeutic targets.A better understanding of the mitochondrial energy metabolism in diabetic cardiomyopathy may help to gain more mechanistic insights and generate more precise mitochondria-oriented therapies to treat this disease.

CircPTEN-MT from PTEN regulates mitochondrial energy metabolism

Phosphatase and tensin homolog(PTEN)is a multifunctional gene involved in a variety of physiological and pathological processes.Circular RNAs(circRNAs)are generated from back-splicing events during mRNA processing and participate in cell biological processes through binding to RNAs or proteins.However,PTEN-related circRNAs are largely unknown.Here,we report that circPTEN-mitochondria(MT)(hsa_circ_0002934)is a circular RNA encoded by exons 3,4,and 5 of PTEN and is a critical regulator of mitochondrial energy metabolism.CircPTEN-MT is localized to mitochondria and physically associated with leucine-rich pentatricopeptide repeat-containing protein(LRPPRC),which regulates posttranscriptional gene expression in mitochondria.Knocking down circPTEN-MT reduces the interaction of LRPPRC and steroid receptor RNA activator(SRA)stem-loop interacting RNA binding protein(SLIRP)and inhibits the polyadenylation of mitochondrial mRNA,which decreases the mRNA level of the mitochondrial complex I subunit and reduces mitochondrial membrane potential and adenosine triphosphate production.Our data demonstrate that circPTEN-MT is an important regulator of cellular energy metabolism.This study expands our understanding of the role of PTEN,which produces both linear and circular RNAs with different and independent functions.

Boosting synergism of chemo- and immunotherapies via switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis by bisphosphonate coordination lipid nanogranules

Conventional chemotherapy based on cytotoxic drugs is facing tough challenges recently following the advances of monoclonal antibodies and molecularly targeted drugs.It is critical to inspire new potential to remodel the value of this classical therapeutic strategy.Here,we fabricate bisphosphonate coordination lipid nanogranules(BC-LNPs)and load paclitaxel(PTX)to boost the chemo-and immuno-therapeutic synergism of cytotoxic drugs.Alendronate in BC-LNPs@PTX,a bisphosphonate to block mevalonate metabolism,works as both the structure and drug constituent in nanogranules,where alendronate coordinated with calcium ions to form the particle core.The synergy of alendronate enhances the efficacy of paclitaxel,suppresses tumor metastasis,and alters the cytotoxic mechanism.Differing from the paclitaxel-induced apoptosis,the involvement of alendronate inhibits the mevalonate metabolism,changes the mitochondrial morphology,disturbs the redox homeostasis,and causes theaccumulation of mitochondrial ROS and lethal lipid peroxides(LPO).These factors finally trigger the ferroptosis of tumor cells,an immunogenic cell death mode,which remodels the suppressive tumor immune microenvironment and synergizes with immunotherapy.Therefore,by switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis,BC-LNPs@PTX provides new insight into the development of cytotoxic drugs and highlights the potential of metabolism regulation in cancer therapy.

Therapeutic potential of alkaloid extract from Codonopsis Radix in alleviating hepatic lipid accumulation: insights into mitochondrial energy metabolism and endoplasmic reticulum stress regulation in NAFLD mice

Alkaloids are a class of naturally occurring bioactive compounds that are widely distributed in various food sources and Traditional Chinese Medicine.This study aimed to investigate the therapeutic effects and underlying mechanisms of alkaloid extract from Codonopsis Radix(ACR)in ameliorating hepatic lipid accumulation in a mouse model of non-alcoholic fatty liver disease(NAFLD)induced by a high-fat diet(HFD).The results revealed that ACR treatment effectively mitigated the abnormal weight gain and hepatic injury associated with HFD.Furthermore,ACR ameliorated the dysregulated lipid metabolism in NAFLD mice,as evidenced by reductions in serum triglyceride,total cholesterol,and low-density lipoprotein levels,accompanied by a concomitant increase in the high-density lipoprotein level.ACR treatment also demonstrated a profound anti-oxidative effect,effectively alleviating HFD-induced oxidative stress and promoting ATP production.These effects were achieved through the up-regulation of the activities of mitochondrial electron transfer chain complexes Ⅰ,Ⅱ,Ⅳ,and Ⅴ,in addition to the activation of the AMPK/PGC-1α pathway,suggesting that ACR exhibits therapeutic potential in alleviating the HFD-induced dysregulation of mitochondrial energy metabolism.Moreover,ACR administration mitigated HFD-induced endoplasmic reticulum(ER)stress and suppressed the overexpression of ubiquitin-specific protease 14(USP14)in NAFLD mice.In summary,the present study provides compelling evidence supporting the hepatoprotective role of ACR in alleviating lipid deposition in NAFLD by improving energy metabolism and reducing oxidative stress and ER stress.These findings warrant further investigation and merit the development of ACR as a potential therapeutic agent for NAFLD.

Glutamate Impairs Mitochondria Aerobic Respiration Capacity and Enhances Glycolysis in Cultured Rat Astrocytes

Objective To study the effect of glutamate on metabolism, shifts in glycolysis and lactate release in rat astrocytes. Methods After 10 days, secondary cultured astrocytes were treated with 1 mmol/L glutamate for 1 h, and the oxygen consumption rates （OCR） and extra cellular acidification rate （ECAR） was analyzed using a Seahorse XF 24 Extracellular Flux Analyzer. Cell viability was then evaluated by MTT assay. Moreover, changes in extracellular lactate concentration induced by glutamate were tested with a lactate detection kit. Results Compared with the control group, treatment with 1 mmol/L glutamate decreased the astrocytes’ maximal respiration and spare respiratory capacity but increased their glycolytic capacity and glycolytic reserve. Further analysis found that 1-h treatment with different concentrations of glutamate （0.1-1 mmol/L） increased lactate release from astrocytes, however the cell viability was not affected by the glutamate treatment. Conclusion The current study provided direct evidence that exogenous glutamate treatment impaired the mitochondrial respiration capacity of astrocytes and enhanced aerobic glycolysis, which could be involved in glutamate injury or protection mechanisms in response to neurological disorders.

Effects of electroacupuncture pretreatment on mitochondrial energy metabolism in the rats with myocardial ischemia reperfusion

Objective:To explore the effects of electroacupuncture pretreatment on mitochondrial energy metabolism in the rats with myocardial ischemia reperfusion injury(MIRI).Methods:A total of 60 SPF Wistar rats were randomly divided into a sham-operation group(sham group),a myocardial ischemia reperfusion injury group(MIRI group)and an electroacupuncture pretreatment group(EA group),20 rats in each one.The rats in the sham group and the MIRI group were binded for 7 days,once a day,20 min each time.On the 8th day,the sample was collected after the heart exposed for 50 min in thoractomy in the sham group and the sample was collected after ischemia for 20 min and reperfusion for 30 min in thoractomy in the MIRI group.In the EA group,the pretreatment intervention with electroacupuncture was applied at"Neiguan(内关PC6)","Guanyuan(关元CV4)"and"Zusanli(足三里ST36)"in the rats for 7 days,once a day,20 min each time.On the 8th day,after ischemia for 20 min and reperfusion for 30 min in thoractomy,the sample was collected in the EA group.The changes in STⅡsegment of electroacardiogram(ECG)were observed and measured.Using enzymelinked immunosorbent assay(ELISA),the concentrations of cardiac troponin T(cTnT)and cardiac troponin I(cTnl)were detected.Using nitro blue tetrazolium chloride monohydrate(NBT)staining,the myocardial infarction weight percentage was measured.Using ELISA,the concentrations of mitochondrial adenosine monophosphate(AMP),adenosine diphosphate(ADP)and adenosine triphosphate(ATP)were detected.Results:(1)STⅡchanges:in 20 min of ligation,compared with the sham group,the STⅡsegment of electrocardiograph(ECG)was elevated significantly in the MIRI group and EA group(both P<0.01),but the elevation range in the EA group was lower than that of the MIRI group(P<0.01).After reperfusion for30 min,the STⅡsegment was fallen by over 50%in the MIRI group and the EA group.Simultaneously,the STⅡsegment in the EA group was lower than that of the MIRI group(P<0.01).(2)Regarding myocardial infarction weight percentage,compared with the sham group,the infarction weight was larger in the MIRI group and the EA group(both P<0.05)and the infarction weight in the EA group was lower than that of the MIRI group(P<0.05).(3)Regarding the levels of serum cTnt and cTnI,compared with the sham group,the levels of serum cTnT and cTnI were higher in the MIRI group and the EA group(all P<0.01)and the levels of cTnT and cTnI in the EA group were lower than that of the MIRI group(both P<0.01).(4)Regarding the concentrations of AMP,ADP and ATP,compared with the sham group,ATP concentration was lower in the MIRI group and the EA group(both P<0.01)and the concentrations of AMP and ADP were higher(P<0.05,P<0.01).Compared with the MIRI group,ATP concentration was higher in the EA group(P<0.05)and the concentrations of AMP and ADP were lower(both P<0.01).Conclusions:Electroacupuncture pretreatment reduces the elevation of ECG STⅡsegment,decreases the concentrations of myocardial injury markers,cTnT and cTnI and regulates the transfer among AMP,ATP and ADP.The protective effect of electroacupuncture pretreatment may result from the regulation of mitochondrial energy metabolism.

Baoyuan decoction alleviates myocardial infarction through the regulation of metabolic dysfunction and the mitochondria-dependent caspase-9/3 pathway

Objective:Baoyuan decoction(BYD)is a traditional Chinese formula with myocardial protection efficacy validated by modern pharmacological tests.The present study aimed to investigate the effect and mechanism of BYD on alleviating myocardial infarction(MI).Methods:Nuclear magnetic resonance-based serum and urinary metabolomics were employed to explore the metabolic regulation effects of BYD in rats with MI induced by left anterior descending ligation.Oxygen-glucose deprivation/recovery(OGD/R)model in H9c2 cells and multiple molecular biology approaches were used to clarify the underlying action mechanisms of BYD.Results:BYD treatment recovered the serum and urinary metabolite profiles of the MI rats toward normal metabolic status and significantly improved mitochondrial energy metabolism and apoptosis pathways perturbed by MI.Analysis of the molecular mechanism of BYD indicated that it suppressed OGD/R-induced H9c2 cell apoptosis in a concentration-dependent manner by inhibiting the mitochondria-dependent caspase-9/3-poly ADP-ribose polymerase pathway.Conclusions:Our results demonstrate that BYD protects against myocardial apoptosis via the mitochondrial metabolic and apoptosis pathways.They also provide novel insights into the clinical application of BYD for the treatment of ischemic heart diseases.

PGC-1α promotes mitochondrial respiration and biogenesis during the differentiation of hiPSCs into cardiomyocytes

Although it is widely accepted that human induced pluripotent stem cell-derived cardiomyocytes(hiPSC-CMs)are readily available,robustly reproducible,and physiologically appropriate human cells for clinical applications and research in the cardiovascular field,hiPSC-CMs cultured in vitro retain an immature metabolic phenotype that limits their application,and little is known about the underlying molecular mechanism controlling mitochondrial metabolic maturation during human induced pluripotent stem cells(hiPSCs)differentiation into cardiomyocytes.In this study,we found that peroxisome proliferator-activated receptor g coactivator-1α(PGC-1α)played an important role in inducing mitochondrial biogenesis and establishing oxidative phosphorylation(OXPHOS)during the cardiac differentiation of hiPSCs.Knocking down PGC-1α by siRNA impaired mitochondrial respiration,while upregulating PGC-1α by ZLN005 promoted mitochondrial biosynthesis and function by regulating the expression of downstream genes involved in mitochondrial dynamics and oxidative metabolism in hiPSCCMs.Furthermore,we found that estrogen-related receptor a(ERRa)was required for the induction of PGC-1α stimulatory effects in hiPSC-CMs.These findings provide key insights into the molecular control of mitochondrial metabolism during cardiac differentiation and may be used to generate more metabolically mature cardiomyocytes for application.

Abnormal energy metabolism and tau phosphorylation in the brains of middle-aged mice in response to atmospheric PM2.5 exposure

In light of the accelerated aging of the global population and the deterioration of the atmosphere pollution, we sought to clarify the potential mechanisms by which fine particulate matter（PM_（2.5）） can cause cognitive impairment and neurodegeneration through the alteration of mitochondrial structure and function. The results indicate that PM_（2.5） inhalation reduces ATP production by disrupting the aerobic tricarboxylic acid cycle and oxidative phosphorylation, thereby causing the hypophosphorylation of tau in the cortices of middle-aged mice. Furthermore, excessive reactive oxygen species generation was involved in the impairment. Interestingly, these alterations were partially reversed after exposure to PM_（2.5） ended. These findings clarify the mechanism involved in mitochondrial abnormality-related neuropathological dysfunction in response to atmospheric PM_（2.5） inhalation and provide an optimistic sight for alleviating the adverse health outcomes in polluted areas.

High dietary lipid level promotes low salinity adaptation in the marine euryhaline crab(Scylla paramamosain)

The physiological processes involved in adaptation to osmotic pressure in euryhaline crustaceans are highly energy demanding,but the effects of dietary lipids(fat)on low salinity adaptations have not been well evaluated.In the present study,a total of 120 mud crabs(Scylla paramamosain,BW=17.87±1.49 g)were fed control and high-fat(HF)diets,at both medium salinity(23‰)and low salinity(4‰)for 6 wk,and each treatment had 3 replicates with each replicate containing 10 crabs.The results indicated that a HF diet significantly mitigated the reduction in survival rate,percent weight gain and feed efficiency induced by low salinity(P<0.05).Low salinity lowered lipogenesis and activated lipolysis resulting in lipid depletion in the hepatopancreas of mud crabs(P<0.05).Thus,HF diets enhanced the process of lipolysis to supply more energy.In the gills,low salinity and the HF diet increased the levels of mitochondrial biogenesis markers,the activity of mitochondrial complexes,and the expression levels of genes related to energy metabolism(P<0.05).Consequently,the positive effects of the HF diet on energy metabolism in mud crabs at low salinity promoted osmotic pressure regulation.Specifically,significantly higher haemolymph osmotic pressure and inorganic ion content,as well as higher osmotic pressure regulatory enzyme activity in gills,and gene and protein expression levels of NaK-ATPase were observed in crabs fed the HF diet at low salinity(P<0.05).In summary,high dietary lipid levels improved energy provision to facilitate mitochondrial biogenesis,which increased ATP provision for osmotic pressure regulation of mud crabs.This study also illustrates the importance of dietary lipid nutrition supplementation for low salinity adaptations in mud crabs.

Resveratrol promotes the survival and neuronal differentiation of hypoxia-conditioned neuronal progenitor cells in rats with cerebral ischemia

Hypoxia conditioning could increase the survival of transplanted neuronal progenitor cells(NPCs)in rats with cerebral ischemia but could also hinder neuronal differentiation partly by suppressing mitochondrial metabolism.In this work,the mitochondrial metabolism of hypoxia-conditioned NPCs(hcNPCs)was upregulated via the additional administration of resveratrol,an herbal compound,to resolve the limitation of hypoxia conditioning on neuronal differentiation.Resveratrol was first applied during the in vitro neuronal differentiation of hcNPCs and concurrently promoted the differentiation,synaptogenesis,and functional development of neurons derived from hcNPCs and restored the mitochondrial metabolism.Furthermore,this herbal compound was used as an adjuvant during hcNPC transplantation in a photothrombotic stroke rat model.Resveratrol promoted neuronal differentiation and increased the long-term survival of transplanted hcNPCs.18-fluorine fluorodeoxyglucose positron emission tomography and rotarod test showed that resveratrol and hcNPC transplantation synergistically improved the neurological and metabolic recovery of stroke rats.In conclusion,resveratrol promoted the neuronal differentiation and therapeutic efficiency of hcNPCs in stroke rats via restoring mitochondrial metabolism.This work suggested a novel approach to promote the clinical translation of NPC transplantation therapy.

The association between disruption of the circadian rhythm and aggravation of colitis in mice

Delayed recovery from ulcerative colitis is mainly due to impaired healing of the intestinal epithelium after inflammation.The circadian rhythmcontrols cell proliferation and energy metabolism.However,the role of circadian genes in inflammatory bowel disease is largely unknown.The purpose of this study was to investigate whether disrupting the circadian rhythm in mice can worsen colitis by altering mitochondrial energy metabolism.Mice in the experimental groups were under physiologic stress with an 8-h light shift jet-lag schedule every 3 days,whereas those in the control group were not.Subsequently,half of the mice in the control and jet-lagged groups were given dextran sodium sulfate(DSS)to induce colitis.Mice in each group were euthanized at zeitgeber time(ZT)0,ZT4,ZT8,ZT12,ZT16,and ZT20.To investigate the effects of jet lag on the mice,colon specimens were subjected to hematoxylin and eosin staining to analyse mRNA and protein expression of core circadian clock genes(Bmal1,Clock,Per1,Per2,Cry1,Cry2,and Nr1d1).We analysed the mitochondrial morphology,adenosine triphosphate(ATP)levels,and the expression of dynamin-related protein 1(Drp1)and ser637-phosphorylated(p)-Drp1,which are closely related to ATP production.We further investigated the effect of PER2 knockdown in the colon epithelial cells(CCD 841 CoN)by measuring ATP and cell proliferation levels.Disrupting the circadian rhythm changed the oscillation of clock genes in the colon of mice,altered the mitochondrial morphology of the colon specimens,decreased the expression of p-Drp1,reduced ATP production,and exacerbated inflammatory responses in mice with DSS-induced colitis.Additionally,silencing of PER2 in the colon epithelial cells reduced ATP production and cell proliferation.Disrupting the circadian rhythm in mice decreases mitochondrial energy metabolism in the colon and exacerbates symptoms of colitis.