Neural stem cell-derived exosomes promote mitochondrial biogenesis and restore abnormal protein distribution in a mouse model of Alzheimer's disease

Mitochondrial dysfunction is a hallmark of Alzheimer’s disease.We previously showed that neural stem cell-derived extracellular vesicles improved mitochondrial function in the cortex of AP P/PS1 mice.Because Alzheimer’s disease affects the entire brain,further research is needed to elucidate alterations in mitochondrial metabolism in the brain as a whole.Here,we investigated the expression of several important mitochondrial biogenesis-related cytokines in multiple brain regions after treatment with neural stem cell-derived exosomes and used a combination of whole brain clearing,immunostaining,and lightsheet imaging to clarify their spatial distribution.Additionally,to clarify whether the sirtuin 1(SIRT1)-related pathway plays a regulatory role in neural stem cell-de rived exosomes interfering with mitochondrial functional changes,we generated a novel nervous system-SIRT1 conditional knoc kout AP P/PS1mouse model.Our findings demonstrate that neural stem cell-de rived exosomes significantly increase SIRT1 levels,enhance the production of mitochondrial biogenesis-related fa ctors,and inhibit astrocyte activation,but do not suppress amyloid-βproduction.Thus,neural stem cell-derived exosomes may be a useful therapeutic strategy for Alzheimer’s disease that activates the SIRT1-PGC1αsignaling pathway and increases NRF1 and COXIV synthesis to improve mitochondrial biogenesis.In addition,we showed that the spatial distribution of mitochondrial biogenesis-related factors is disrupted in Alzheimer’s disease,and that neural stem cell-derived exosome treatment can reverse this effect,indicating that neural stem cell-derived exosomes promote mitochondrial biogenesis.

Characterization,expression dynamics,and potential function of OPA1 for regulation of mitochondrial morphology during spermiogenesis in Phascolosoma esculenta

Mitochondria undergo morphological changes during spermatogenesis in some animals.The mechanism and role of mitochondrial morphology regulation,however,remain somewhat unclear.In this study,we analyzed the molecular characteristics,expression dynamics and subcellular localization of optic atrophy protein 1(OPA1),a mitochondrial fusion and cristae maintenance-related protein,to reveal the possible regulatory mechanisms underlying mitochondrial morphology in Phascolosoma esculenta spermiogenesis.The full-length cDNA of the P.esculenta opa1 gene(Pe-opa1)is 3743 bp in length and encodes 975 amino acids.The Pe-OPA1 protein is highly conservative and includes a transmembrane domain,a GTPase domain,two helical bundle domains,and a lipid-interacting stalk.Gene and protein expression was higher in the coelomic fluid(a site of spermatid development)of male P.esculenta and increased first and then decreased from March to December.Moreover,their expression during the breeding stage was significantly higher than during the non-breeding stage,suggesting that Pe-OPA1 is involved in P.esculenta reproduction.The Pe-OPA1 protein was more abundant in components consisting of many spermatids than in components without,indicating that Pe-OPA1 mainly plays a role in the spermatid in coelomic fluid.Moreover,Pe-OPA1 was mainly detected in the spermatid mitochondria.Immunofluorescence experiments showed that the Pe-OPA1 are constitutively expressed and co-localized with mitochondria during spermiogenesis,suggesting its involvement in P.esculenta spermiogenesis.These results provide evidence for Pe-OPA1's involvement in the regulation of mitochondrial morphology during spermiogenesis.

Transcriptional Regulation of 10 Mitochondrial Genes in Different Tissues of NCa CMS System in Brassica napus L. and Their Relationship with Sterility

Northern blot analysis was conducted with mitochondrial RNA from seedling leaves, floral buds, and developing seeds of NCa CMS, maintainer line and fertile F1 using ten mitochondrial genes as probes. The results revealed that 9 out of the 10 mitochondrial genes, except for atp6, showed no difference in different tissues of the corresponding materials of NCα CMS system and that they might be constitutively expressed genes. Eight genes, such as orf139, orf222, atpl, cox1, cox2, cob, rm5S, and rm26S, showed no difference among the three tissues of all the materials detected. So the expression of these eight genes was not regulated by nuclear genes and was not tissue-specific. The transcripts of atp9 were identical among different tissues, but diverse among different materials, indicating that transcription of atp9 was neither controlled by nuclear gene nor tissue-specific. Gene atp6 displayed similar transcripts with the same size among different tissues of all the materials but differed in abundance among tissues of corresponding materials and its expression might be tissue-specific under regulation of nuclear gene. Moreover, three transcripts of orf222 were detected in the floral buds of NCa cms and fertile F1, but no transcript was detected in floral buds of the maintainer line.The transcription of orf139 was similar to that of orf222 but only two transcripts of 0.8 kb and 0.6 kb were produced. The atp9 probe detected a single transcript of 0.6 kb in NCa cms and in maintainer line and an additional transcript of 1.2 kb in fertile F1. The relationship of expression of orf222, orf139, and atp9 with NCa sterility was discussed.

Syringic acid improves oxidative stress and mitochondrial biogenesis in the liver of streptozotocin-induced diabetic rats

Objective:To determine the effects of syringic acid on hepatic damage in diabetic rats.Methods:Diabetes was induced by streptozotocin.Diabetic rats were given syringic acid at doses of 25,50 and 100 mg/kg by oral gavage for 6 weeks.Syringic acid effects on the liver were evaluated by examination of plasma biochemical parameters,and pathological study.In addition,biomarkers of lipid peroxidation and antioxidant status of liver tissues were assessed.Real time-PCR was performed to investigate the m RNA expression levels of mitochondrial biogenesis indices in different groups.Results:Syringic acid significantly attenuated the increase in most of plasma biochemical parameters in diabetic rats.Moreover,syringic acid treatment increased the catalase activity while it reduced the superoxide dismutase activity and hepatic malondialdehyde level in diabetic rats.There was no difference between the glutathione content of the treated and untreated groups.These findings were supported by alleviation of histopathological damages in the syringic acid-treated groups compared to the untreated diabetic group.Syringic acid also significantly upregulated the hepatic m RNA expression of PGC-1α,NRF-1,and NRF-2 and increased the mtD NA/nD NA ratio in diabetic rats.Conclusions:Syringic acid can be considered as a suitable candidate against hepatic complications since it can reduce oxidative damages in diabetic cases.Furthermore,it has the potential of targeting hepatic mitochondria in diabetes.

Antibiotics Friend and Foe: “From Wonder Drug to Causing Mitochondrial Dysfunction, Disrupting Human Microbiome and Promoting Tumorigenesis”

Mitochondria are evolutionary bacteria that are dynamic intracellular organelles involved in many vital cellular functions. However, modern medicine has fallen prey to misuse and over-usage of antibiotics. This misuse can damage the mitochondrion, alter host antibiotic interactions, and cause serious pathophysiologic conditions. We believe this leads to mitochondrial dysfunction, which may promote tumorigenesis and neurodegeneration. This opinion commentary’s goal is to bring awareness of this important hot topic to the medical community before induced modern plagues are irreversible.

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.

SIRT3 regulates mitochondrial biogenesis in aging-related diseases

Sirtuin 3(SIRT3),the main family member of mitochondrial deacetylase,targets the majority of substrates controlling mitochondrial biogenesis via lysine deacetylation and modulates important cellular functions such as energy metabolism,reactive oxygen species production and clearance,oxidative stress,and aging.Deletion of SIRT3 has a deleterious effect on mitochondrial biogenesis,thus leading to the defect in mitochondrial function and insufficient ATP production.Imbalance of mitochondrial dynamics leads to excessive mitochondrial biogenesis,dampening mitochondrial function.Mitochondrial dysfunction plays an important role in several diseases related to aging,such as cardiovascular disease,cancer and neurodegenerative diseases.Peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PGC1α)launches mitochondrial biogenesis through activating nuclear respiratory factors.These factors act on genes,transcribing and translating mitochondrial DNA to generate new mitochondria.PGC1αbuilds a bridge between SIRT3 and mitochondrial biogenesis.This review described the involvement of SIRT3 and mitochondrial dynamics,particularly mitochondrial biogenesis in agingrelated diseases,and further illustrated the role of the signaling events between SIRT3 and mitochondrial biogenesis in the pathological process of aging-related diseases.

Importance of Mitochondrial-Related Genes in Dilated Cardiomyopathy Based on Bioinformatics Analysis

We designed this study to identify potential key protein interaction networks,genes,and correlated pathways in dilated cardiomyopathy(DCM)via bioinformatics methods.We selected the GSE3586 microarray dataset,consisting of 15 dilated cardiomyopathic heart biopsy samples and 13 nonfailing heart biopsy samples.Initially,the GSE3586 dataset was downloaded and was analyzed with the limma package to identify differentially expressed genes(DEGs).A total of 172 DEGs consisting of 162 upregulated genes and ten downregulated genes in DCM were selected by the criterion of adjusted P values less than 0.01 and the log2-fold change of 0.6 or greater.Gene Ontology functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis were performed to view the biological processes,cellular components,molecular function,and KEGG pathways of the DEGs.Next,protein-protein interactions were constructed,and the hub protein modules were identifi ed.Then we selected the key genes DLD,UQCRC2,DLAT,SUCLA2,ATP5A1,PRDX3,FH,SDHD,and NDUFV1,which are involved in a wide range of biological activities,such as the citrate cycle,oxidation-reduction processes and cellular respiration,and energy derivation by oxidation of organic compounds in mitochondria.Finally,we found that currently there are no related gene-targeting drugs after exploring the predicted interactions between key genes and drugs,and transcription factors.In conclusion,our study provides greater understanding of the pathogenesis and underlying molecular mechanisms in DCM.This contributes to the exploration of potential gene therapy targets.

Nuclear pseudogenes of mitochondrial DNA as a variable part of the human genome

Novel pseudogenes homologous to the mitochondrial(mt) 16S rRNA gene were detected via different approaches. Eight pseudogenes were sequenced. Copynumber polymorphism of the mtDNA pseudogenes wasobserved among randomly chosen individuals, and evenamong siblings. A mtDNA pseudogene in the Ychromosome was observed in a YAC clone carrying onlyrepetitive sequence tag site (STS). PCR screening of human yeast artificial chromosome (YAC) libraries showedthat there were at least 5.7×105 hp of the mtDNA pseudogenes in each haploid nuclear genome. Possible involvement of the mtDNA pseudogenes in the variable part ofthe human nuclear genome is discussed.

Implications of mitochondrial DNA mutations and mitochondrial dysfunction in tumorigenesis

Alterations in oxidative phosphorylation resulting from mitochondriai dysfunction have long been hypothesized to be involved in tumorigenesis. Mitochondria have recently been shown to play an important role in regulating both programmed cell death and cell proliferation. Furthermore, mitochondrial DNA （mtDNA） mutations have been found in various cancer cells. However, the role of these mtDNA mutations in tumorigenesis remains largely unknown. This review focuses on basic mitochondrial genetics, mtDNA mutations and consequential mitochondrial dysfunction associated with cancer. The potential molecular mechanisms, mediating the pathogenesis from mtDNA mutations and mitochondrial dysfunction to tumorigenesis are also discussed.

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.

Species identification and phylogenetic analysis of genus Nassarius(Nassariidae)based on mitochondrial genes

Genus Nassarius contains many subgenera, such as Zeuxis, Telasco, Niotha, Varicinassa, Plicarcularia, Nassarius s. str. and Reticunassa. On the basis of morphological characteristics of the shell and radula and sequences of mitochondrial cytochrome oxidase subunit I (COI) and 16S rRNA genes, Nassarius specimens collected from the South China Sea were identified and phylogenetically analyzed. Although Nassarius sp. and Nassarius (Varicinassa) variciferus were morphologically different in their shells, few variations were found among their radular teeth and sequences of mtCOI and mt16S RNA genes. Therefore, Nassarius sp. should be classified as N. (Varicinassa) variciferus. Nassarius (Zeuxis) sp. has only a subtle difference from Nassarius (Zeuxis) algidus on the shell, but it shows obvious differences in radular teeth and DNA sequence, indicating that they are two distinct species. Sequence divergence of mtCOI and mt16S RNA genes within Nassarius species was much lower than that between species, suggesting that these two genes are suitable for Nassarius species identification. Phylogenetic analysis (neighbor-joining and maximum parsimony) based on mtCOI and mt16S rRNA genes revealed the presence of two groups in genus Nassarius and a closest relationship between subgenera Zeuxis and Telasco. Species of subgenus Plicarcularia did not form a single clade. The molecular phylogeny was not congruent with the previous morphological phylogeny. The subgeneric divisions of genus Nassarius appear to be uncertain and unreliable.

Genomic Analysis of Mitochondrial Carrier Genes in the Bombyx mori

This study is performed to investigate the mitochondrial carrier gene family in silkworm genome. In total, 30 genes are identified and claded into eight well-conserved groups. Gene duplication contributes to the expansion and complexity of this family. Diverse expression patterns suggest their functional differentiation. Analyses of the sitespecific profiles reveal critical amino acid residues for functional divergence. This study highlights the molecular evolution of the mitochondrial carrier gene family in silkworm and may provide a starting point for further experimental verification.

Differential RNA Editing of Mitochondrial Genes in WA-Cytoplasmic Based Male Sterile Line Pusa 6A, and Its Maintainer and Restorer Lines

RNA editing changes the nucleotides at the transcript level of mitochondrial genes which results in synthesis of functional proteins.This study was designed to find the editing sites which could be implicated in male fertility restoration and to develop editing based markers for differentiation of cytoplasmic male sterility and maintainer lines from each other.DNA and RNA from young panicles were isolated from three-line system of hybrid rice PRH10,wild abortive(WA)cytoplasm based male sterile(A line Pusa 6A),maintainer(B line Pusa 6B)and restorer(R line PRR78)lines.Pusa 6A and PRR78 having the same WA cytoplasm are allo-nuclear and iso-cytpolasmic lines.The genomic and cDNA amplicons for eight mitochondrial genes(18SrRNA,atp6,atp9,cobII,coxI,coxIII,nadI and rps3)were sequenced and compared.Differences in genomic and cDNA sequences were considered as editing.Two hundred and thirty editing sites having base substitution or insertion/deletion were identified with the highest in 18SrRNA(5.74%)and the lowest in coxI(0.60%).The highest editing sites were observed in fertile maintainer Pusa 6B followed by PRR78 and Pusa 6A,of which random five editing sites in five different rice mitochondrial transcripts namely atp9,cobII,coxIII,rps3 and 18SrRNA were chosen and validated through cleaved amplified polymorphism sequence(CAPS)analysis and found to be partially edited in four genes.The identical editing sites of different mitochondrial genes from maintainer and restorer lines might reflect their possible contribution to fertility restoration of sterile WA cytoplasm.

Polymorphism of mitochondrial tRNA genes associated with the number of pigs born alive

Background: Mutations in mitochondrial tRNA genes have been widely reported association with human reproductions.It is also important to explore the effect on the number of piglets born alive(NBA).Here,1017 sows were used to investigate the association between polymorphisms in mitochondrial tRNA genes and NBA.Results: In total,16 mutations were found in mitochondrial tRNA genes,of which 13 mutations were significantly associated with NBA(P < 0.05).The reproductions of mutant carriers were significantly greater than that of wild carriers by 0.989 piglets born alive/sow farrowing.To test whether the mutations altered the structure of mitochondrial tRNAs,the secondary and tertiary structures were predicted.In result,C2255 T changed the secondary structure of t RNA-Val by elongating the T stem and shrinking the T loop,and C2255 T and G2259 A in the tRNA-Val gene,C6217 T and T6219 C in the tRNA-Ala gene,and T15283 C in the tRNA-Glu gene altered the tertiary structure of their tRNAs,respectively by changing the folding form of the T arm,and C16487 T in the tRNA-Thr gene changed the tertiary structure of mitochondrial tRNA-Thr by influencing the folding form of the acceptor arm.Conclusions: Results highlight the effect of mitochondrial tRNA genes on the number of piglets born alive,and suggest that polymorphic sites of the tRNA genes be genetic markers for selection of pig reproduction.

THE PATHOGENESIS OF EXPERIMENTAL MODEL OF MITOCHONDRIAL MYOPATHY INDUCED BY GERMANIUM DIOXIDE

Objective. The purpose of the study was to build up an animal model of mitochondrial myopathy in order to analyse the pathogenesis of the disease. Methods. The skeletal muscles from Wistar rats treated with germanium dioxide for 24 weeks were analysed by histopathologic and electron- microscopic studies. A quantitative analysis was carried out in mitochondrial DNAs of these samples. The biological function of the model was determined. Results. An animal model of mitochondrial myopathy was built up, in which oxygen free radicals were increased and mitochondrial DNA copies were decreased contrasted with controls. Conclusion. It suggested that environmental toxin may play a role in the pathogenesis of mitochondrial myopathy. The increase of oxygen free radicals is an important link causing the disease.

Peripheral mitochondrial DNA as a neuroinflammatory biomarker for major depressive disorder

In the pathogenesis of major depressive disorder, chronic stress-related neuroinflammation hinders favorable prognosis and antidepressant response. Mitochondrial DNA may be an inflammatory trigger, after its release from stress-induced dysfunctional central nervous system mitochondria into peripheral circulation. This evidence supports the potential use of peripheral mitochondrial DNA as a neuroinflammatory biomarker for the diagnosis and treatment of major depressive disorder. Herein, we critically review the neuroinflammation theory in major depressive disorder, providing compelling evidence that mitochondrial DNA release acts as a critical biological substrate, and that it constitutes the neuroinflammatory disease pathway. After its release, mitochondrial DNA can be carried in the exosomes and transported to extracellular spaces in the central nervous system and peripheral circulation. Detectable exosomes render encaged mitochondrial DNA relatively stable. This mitochondrial DNA in peripheral circulation can thus be directly detected in clinical practice. These characteristics illustrate the potential for mitochondrial DNA to serve as an innovative clinical biomarker and molecular treatment target for major depressive disorder. This review also highlights the future potential value of clinical applications combining mitochondrial DNA with a panel of other biomarkers, to improve diagnostic precision in major depressive disorder.

Mitochondrial therapeutics and mitochondrial transfer for neurodegenerative diseases and aging

Mitochondrial dysfunction and neurodegeneration:Progressive neurodegenerative diseases affect a significant proportion of the population;in a single year,there are as many as 276 million disabilities and 9 million deaths as a result of neurological diseases.

Unveiling mitochondrial mysteries:Exploring novel tRNA variants in type 2 diabetes mellitus

The recent study of Ding et al provides valuable insights into the functional implications of novel mitochondrial tRNATrp and tRNASer(AGY)variants in type 2 diabetes mellitus(T2DM).This editorial explores their findings,highlighting the role of mitochondrial dysfunction in the pathogenesis of T2DM.By examining the molecular mechanisms through which these tRNA variants contribute to disease progression,the study introduces new targets for therapeutic strategies.We discuss the broader implications of these results,emphasizing the importance of understanding mitochondrial genetics in addressing T2DM.