Selenium-enriched Cardamine violifolia protects against sepsis-induced intestinal injury by regulating mitochondrial fusion in weaned pigs

Sepsis is a life-threatening organ dysfunction caused by the dysregulated response of the host to an infection, and treatments are limited. Recently, a novel selenium source, selenium-enriched Cardamine violifolia(SEC) has attracted much attention due to its anti-inflammatory and antioxidant properties, but little is known about its role in the treatment of sepsis. Here, we found that SEC alleviated LPS-induced intestinal damage, as indicated by improved intestinal morphology, and increased disaccharidase activity and tight junction protein expression. Moreover, SEC ameliorated the LPS-induced release of pro-inflammatory cytokines, as indicated by decreased IL-6 level in the plasma and jejunum. Moreover, SEC improved intestinal antioxidant functions by regulating oxidative stress indicators and selenoproteins. In vitro, TNF-α-challenged IPEC-1 cells were examined and showed that selenium-enriched peptides, which are the main functional components extracted from Cardamine violifolia(CSP), increased cell viability, decreased lactate dehydrogenase activity and improved cell barrier function. Mechanistically, SEC ameliorated LPS/TNF-α-induced perturbations in mitochondrial dynamics in the jejunum and IPEC-1 cells. Moreover, CSPmediated cell barrier function is primarily dependent on the mitochondrial fusion protein MFN2 but not MFN1. Taken together,these results indicate that SEC mitigates sepsis-induced intestinal injury, which is associated with modulating mitochondrial fusion.

Mitochondrial dysfunction and quality control lie at the heart of subarachnoid hemorrhage

The dramatic increase in intracranial pressure after subarachnoid hemorrhage leads to a decrease in cerebral perfusion pressure and a reduction in cerebral blood flow.Mitochondria are directly affected by direct factors such as ischemia,hypoxia,excitotoxicity,and toxicity of free hemoglobin and its degradation products,which trigger mitochondrial dysfunction.Dysfunctional mitochondria release large amounts of reactive oxygen species,inflammatory mediators,and apoptotic proteins that activate apoptotic pathways,further damaging cells.In response to this array of damage,cells have adopted multiple mitochondrial quality control mechanisms through evolution,including mitochondrial protein quality control,mitochondrial dynamics,mitophagy,mitochondrial biogenesis,and intercellular mitochondrial transfer,to maintain mitochondrial homeostasis under pathological conditions.Specific interventions targeting mitochondrial quality control mechanisms have emerged as promising therapeutic strategies for subarachnoid hemorrhage.This review provides an overview of recent research advances in mitochondrial pathophysiological processes after subarachnoid hemorrhage,particularly mitochondrial quality control mechanisms.It also presents potential therapeutic strategies to target mitochondrial quality control in subarachnoid hemorrhage.

SIRT3 protects against early brain injury following subarachnoid hemorrhage via promoting mitochondrial fusion in an AMPK dependent manner

Background:Subarachnoid hemorrhage(SAH),an acute cerebrovascular accident,features with its high death and disability rate.Sirtuin3(SIRT3)is a NAD+dependent deacetylase which mainly located in mitochondria.Reduced SIRT3 function was indicated to involve in many disorders of central nervous system.Herein,we aimed to explore the neuroprotective effects of SIRT3 on SAH and to furtherly explore the underlying mechanisms.Methods:Adult C57BL/6 J male mice(8-10 weeks)were used to establish SAH models.The pharmacological agonist of SIRT3,Honokiol(HKL),was injected in an intraperitoneal manner(10 mg/kg)immediately after the operation.Brain edema and neurobehavioral score were assessed.Nissl staining and FJC staining were used to evaluate the extent of neuronal damage.The changes of mitochondria morphology were observed with transmission electron microscopy.Western blot was used for analyzing the protein level of SIRT3 and the downstream signaling molecules.Result:SIRT3 was downregulated after SAH,and additional treatment of SIRT3 agonist HKL alleviated brain edema and neurobehavioral deficits after SAH.Additionally,electron microscopy showed that HKL significantly alleviated the morphological damage of mitochondria induced by SAH.Further studies showed that HKL could increase the level of mitochondrial fusion protein Mfn1 and Mfn2,thus maintaining(mitochondrial morphology),protecting mitochondrial function and promoting neural survival.While,additional Compound C(CC)treatment,a selective AMPK inhibitor,abolished these protective effects.Conclusions:Activation of SIRT3 protects against SAH injury through improving mitochondrial fusion in an AMPK dependent manner.

Crosslink between mutations in mitochondrial genes and brain disorders:implications for mitochondrial-targeted therapeutic interventions

At the present,association of mitochondrial dysfunction and progression of neurological disorders has gained significant attention.Defects in mitochondrial network dynamics,point mutations,deletions,and interaction of pathogenomic proteins with mitochondria are some of the possible underlying mechanisms involved in these neurological disorders.Mitochondrial genetics,defects in mitochondrial oxidative phosphorylation machinery,and reactive oxygen species production might share common crosstalk in the progression of these neurological disorders.It is of significant interests to explore and develop therapeutic strategies aimed at correcting mitochondrial abnormalities.This review provided insights on mitochondrial dysfunction/mutations involved in the progression of Alzheimer’s disease,Huntington’s disease,and epilepsy with a special focus on Parkinson’s disease pathology.Along with the deleterious effects of mitochondrial mutations in aforesaid neurological disorders,this paper unraveled the available therapeutic strategy,specifically aiming to improve mitochondrial dysfunction,drugs targeting mitochondrial proteins,gene therapies aimed at correcting mutant mtDNA,peptide-based approaches,and lipophilic cations.

Mitochondria in Huntington’s disease:implications in pathogenesis and mitochondrial-targeted therapeutic strategies

Huntington’s disease is a genetic disease caused by expanded CAG repeats on exon 1 of the huntingtin gene located on chromosome 4.Compelling evidence implicates impaired mitochondrial energetics,altered mitochondrial biogenesis and quality control,disturbed mitochondrial trafficking,oxidative stress and mitochondrial calcium dyshomeostasis in the pathogenesis of the disorder.Unfortunately,conventional mitochondrial-targeted molecules,such as cysteamine,creatine,coenzyme Q10,or triheptanoin,yielded negative or inconclusive results.However,future therapeutic strategies,aiming to restore mitochondrial biogenesis,improving the fission/fusion balance,and improving mitochondrial trafficking,could prove useful tools in improving the phenotype of Huntington’s disease and,used in combination with genome-editing methods,could lead to a cure for the disease.

Aldehyde dehydrogenase 2 preserves mitochondrial morphology and attenuates hypoxia/reoxygenationinduced cardiomyocyte injury

BACKGROUND:Disturbance of mitochondrial fi ssion and fusion(termed mitochondrial dynamics)is one of the leading causes of ischemia/reperfusion(I/R)-induced myocardial injury.Previous studies showed that mitochondrial aldehyde dehydrogenase 2(ALDH2)conferred cardioprotective effect against myocardial I/R injury and suppressed I/R-induced excessive mitophagy in cardiomyocytes.However,whether ALDH2 participates in the regulation of mitochondrial dynamics during myocardial I/R injury remains unknown.METHODS:In the present study,we investigated the effect of ALDH2 on mitochondrial dynamics and the underlying mechanisms using the H9c2 cells exposed to hypoxia/reoxygenation(H/R)as an in vitro model of myocardial I/R injury.RESULTS:Cardiomyocyte apoptosis was significantly increased after oxygen-glucose deprivation and reoxygenation(OGD/R),and ALDH2 activation largely decreased the cardiomyocyte apoptosis.Additionally,we found that both ALDH2 activation and overexpression significantly inhibited the increased mitochondrial fission after OGD/R.Furthermore,we found that ALDH2 dominantly suppressed dynamin-related protein 1(Drp1)phosphorylation(Ser616)and adenosine monophosphate-activated protein kinase(AMPK)phosphorylation(Thr172)but not interfered with the expression levels of mitochondrial shaping proteins.CONCLUSIONS:We demonstrate the protective effect of ALDH2 against cardiomyocyte H/R injury with a novel mechanism on mitochondrial fission/fusion.

PKM2-mediated neuronal hyperglycolysis enhances the risk of Parkinson's disease in diabetic rats

Epidemiological and animal studies indicate that pre-existing diabetes increases the risk of Parkinson's disease(PD).However,the mechanisms underlying this association remain unclear.In the present study,we found that high glucose(HG)levels in the cerebrospinal fluid(CSF)of diabetic rats might enhance the effect of a subthreshold dose of the neurotoxin 6-hydroxydopamine(6-OHDA)on the development of motor disorders,and the damage to the nigrostriatal dopaminergic neuronal pathway.In vitro,HG promoted the 6-OHDA-induced apoptosis in PC12 cells differentiated to neurons with nerve growth factor(NGF)(NGF-PC12).Metabolomics showed that HG promoted hyperglycolysis in neurons and impaired tricarboxylic acid cycle(TCA cycle)activity,which was closely related to abnormal mitochondrial fusion,thus resulting in mitochondrial loss.Interestingly,HG-induced upregulation of pyruvate kinase M2(PKM2)combined with 6-OHDA exposure not only mediated glycolysis but also promoted abnormal mitochondrial fusion by upregulating the expression of MFN2 in NGF-PC12 cells.In addition,we found that PKM2 knockdown rescued the abnormal mitochondrial fusion and cell apoptosis induced by HGþ6-OHDA.Furthermore,we found that shikonin(SK),an inhibitor of PKM2,restored the mitochondrial number,promoted TCA cycle activity,reversed hyperglycolysis,enhanced the tolerance of cultured neurons to 6-OHDA,and reduced the risk of PD in diabetic rats.Overall,our results indicate that diabetes promotes hyperglycolysis and abnormal mitochondrial fusion in neurons through the upregulation of PKM2,leading to an increase in the vulnerability of dopaminergic neurons to 6-OHDA.Thus,the inhibition of PKM2 and restoration of mitochondrial metabolic homeostasis/pathways may prevent the occurrence and development of diabetic PD.

A facile cell culture device for studying nuclear and mitochondrial response of endothelial cells to hydrostatic pressure

There is no clear consensus regarding how cells respond to hydrostatic pressure. This is largely attributable to the high heterogeneity among cell types and the diverse custom-made devices used in previous studies. The aim of this work was to develop a facile device that could mimic various pressure environments and then delineate the cellular response to pressure stimulus. The device described here achieved both stable and periodic pressurization without oxygen deprivation. The biological utility of the device was assessed using human umbilical vein endothelial cells. We found more stereoscopic nuclear morphology and re-distribution of lamin A/C under high hydrostatic pressure compared to control cells. Mass spectrometry-based proteomics analysis showed significant changes in mitochondria-related pathways. Western blot analysis confirmed that high hydrostatic pressure induced a tendency toward mitochondrial fusion. Increased mitochondrial activity was observed as well. In conclusion, this device can be readily applied in biological research and extend our understanding of cellular mechano-sensation and the associated changes in mitochondrial behaviors.

Mitochondrial dynamic abnormalities in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis(ALS)is the most common motor neuron disease characterized by progressive loss of motor neurons in the brainstem and spinal cord.Currently,there is no cure or effective treatment for ALS and the cause of disease is unknown in the majority of ALS cases.Neuronal mitochondria dysfunction is one of the earliest features of ALS.Mitochondria are highly dynamic organelles that undergo continuous fission,fusion,trafficking and turnover,all of which contribute to the maintenance of mitochondrial function.Abnormal mitochondrial dynamics have been repeatedly reported in ALS and increasing evidence suggests altered mitochondrial dynamics as possible pathomechanisms underlying mitochondrial dysfunction in ALS.Here,we provide an overview of mitochondrial dysfunction and dynamic abnormalities observed in ALS,and discuss the possibility of targeting mitochondrial dynamics as a novel therapeutic approach for ALS.