Mitoepigenetics and drug addiction

Being the center of energy production in eukaryotic cells, mitochondria are also crucial for various cellular processes including intracellular Ca²⁺ signaling and generation of reactive oxygen species (ROS). Mitochondria contain their own circular DNA which encodes not only proteins, transfer RNA and ribosomal RNAs but also non-coding RNAs. The most recent line of evidence indicates the presence of 5-methylcytosine and 5-hydroxymethylcytosine in mitochondrial DNA (mtDNA); thus, the level of gene expression – in a way similar to nuclear DNA – can be regulated by direct epigenetic modifications. Up to now, very little data shows the possibility of epigenetic regulation of mtDNA. Mitochondria and mtDNA are particularly important in the nervous system and may participate in the initiation of drug addiction. In fact, some addictive drugs enhance ROS production and generate oxidative stress that in turn alters mitochondrial and nuclear gene expression. This review summarizes recent findings on mitochondrial function, mtDNA copy number and epigenetics in drug addiction.     

Mitochondrial genomes of Anisakis simplex and Contracaecum osculatum (sensu stricto) – Comparisons with selected nematodes

Anisakid nematodes parasitize mainly fish, marine mammals and/or fish-eating birds, and can be transmitted to a range of fish-eating mammals, including humans, where they can cause gastrointestinal disease linked to larval infection or allergic responses. In spite of the animal and human health significance of these parasites, there are still gaps in our understanding of the systematics, biology, epidemiology and ecology of anisakids. Mitochondrial (mt) DNA provides useful genetic markers for investigations in these areas, but complete mt genomic data have been lacking for most anisakids. In the present study, the mt genomes of Anisakis simplex sensu stricto and Contracaecum osculatum sensu stricto were amplified from genomic DNA by long-range polymerase chain reaction and sequenced using 454 technology. The circular mt genomes of these species were 13,926 and 13,823 bp, respectively, and each of them contained 12 protein-coding, 22 transfer RNA, and 2 ribosomal RNA genes consistent for members of the Ascaridida, Oxyurida, Spirurida, Rhabditida and Strongylida. These mt genomes provide a stepping-stone for future comparative analyses of a range of anisakids and a basis for reinvestigating their genetic relationships. In addition, these markers might be used in prospecting for cryptic species and exploring host affiliations.     

线粒体参与糖尿病肾病发生的研究新进展

糖尿病肾病(DN)是糖尿病远期主要并发症之一,累及肾脏微血管,导致肾功能不可逆损害,并迅速进展至肾病终末期。DN发病机制复杂,目前仍不完全清楚,近期有研究发现,线粒体通过其内DNA水平异常、解偶联蛋白2抗氧化及线粒体抗病毒信号分子调节失衡、钙离子超载等参与了DN发生发展。     

The role of dynamin-related protein 1 in cancer growth: a promising therapeutic target?

Mitochondrial functions are altered in many human diseases including cancer. Development of mitochondria-targeted therapies, either through restoring normal mitochondrial function or promoting mitochondrial-induced cell death, is one of the attractive strategies to improve the outcome of cancer treatment. Recent advances have revealed the important functional involvement of mitochondrial dynamics in cancer biology. Dynamin-related protein 1 (Drp1), a member of the dynamin family of GTPases required for mitochondrial fission, has been found upregulated in certain types of cancers, such as lung and breast cancers. In addition, the roles of Drp1 in cell cycle progression, genome instability, cell migration and apoptosis in cancer cells have also been recently uncovered. These findings raise the possibility of targeting Drp1-mediated mitochondrial fission as an effective therapy for treating cancer. This article explores the function of Drp1 in cancer cells and discusses the theoretical basis for the development of potential targeted therapy.     

Genetic classification of Echinococcus granulosus cysts from humans, cattle and camels in Libya using mutation scanning-based analysis of mitochondrial loci

We genetically classified Echinococcus granulosus from humans, cattle and camels in Libya utilizing DNA regions (designated pcox1 and pnad1) within the cytochrome c oxidase subunit 1 (cox1) and NADH dehydrogenase 1 (nad1) mitochondrial genes, respectively. Polymerase chain reaction (PCR)-based single-strand conformation polymorphism (SSCP) analysis of pcox1 and pnad1 amplicons derived from genomic DNA samples from individual cysts (n = 176) revealed four distinct electrophoretic profiles for each locus. Direct sequencing of selected amplicons representing each of these profiles defined four different sequence types for each locus, which were present in five different combinations (designated haplotypes A–E) amongst all 176 isolates. Phylogenetic analysis of concatenated sequence data for these five haplotypes, together with a range of well-defined reference sequences, inferred that all cyst isolates from humans (n = 55) and a small number from cattle (13% of 38) belonged to the G1–G3 complex of E. granulosus (or E. granulosus sensu stricto), whereas most (87%) cysts from cattle and all 83 of them from camels were linked to the G6–G10 complex (or Echinococcus canadensis). The present study provides a foundation for future large-scale studies of the epidemiology and ecology of E. granulosus in Libya and other African countries.     

Mitochondrial K<Subscript>ATP</Subscript> channel-dependent and -independent phases of ischemic preconditioning against myocardial infarction in the rat

To obtain insight into the role of the mitochondrial ATP-sensitive K(+) (mitoK(ATP)) channel in ischemic preconditioning (PC), we aimed to clarify the mitoK(ATP) channel-dependent phase of PC in two PC protocols with different intervals between PC ischemia and an index ischemia. The possible contribution of mitoK(ATP) channel opening to protein kinase C activation in PC was also examined by Western blotting. Myocardial infarction was induced by 30-min coronary occlusion/2-h reperfusion in rat hearts in situ, and infarct size was expressed as a percentage of the area at risk (% IS/AR). PC was performed with 2 episodes of 5-min ischemia, and each heart was subjected to 30-min ischemia either 5 min or 20 min after PC. At 5 min after PC, both PKC-delta and -epsilon were translocated and the myocardium was protected against infarction (% IS/AR = 28.3 +/- 2.7 % vs. 72.7 +/- 2.2 in controls p < 0.05). Pretreatment with a selective mitoK(ATP) channel blocker, 5-hydroxydecanoate (5-HD, 10 mg/kg), abolished the cardioprotection but not PKC translocation by PC. At 20 min after PC, PKC translocation remained at the same level as that 5 min after PC, but the anti-infarct tolerance was attenuated (%IS/AR = 43.5 +/- 4.7 %). Injection of 5-HD after PC did not affect anti-infarct tolerance at 5 min after PC but abolished the protection at 20 min after PC without any effects on PKC. These results suggest that the mitoK(ATP) channel plays a role in triggering of PC in a PKC-independent manner and that the role of the mitoK(ATP) channel as a mediator of protection is detectable after, but not before, the PC effect starts to decay without a change in the level of PKC translocation in the rat heart.     

The effect of Coenzyme Q10 on reperfusion injury in canine myocardium

The mechanism of mitochondrial damage during reperfusion injury of ischemic myocardium was studied using mongrel dogs in vivo and isolated mitochondria in vitro. Seventy-seven adult dogs were divided into three groups: the control group (n = 38), the Coenzyme Q10 (CoQ10)-5 mg group (n = 24), and the CoQ10-15 mg group (n = 15). In the control group, the left anterior descending coronary artery (LAD) of the dog was occluded for 15 min followed by 5 min of reperfusion after 40 min of premedication with physiological saline. In both CoQ10 groups, 5 mg/kg or 15 mg/kg of CoQ10 was infused intravenously for 20 min and then physiological saline was administered for 20 min before 15 min occlusion of the LAD. Subsequently, reperfusion was allowed for 5 min. Each group was further divided into two subgroups depending on the presence (arrhythmia group) or the absence (non-arrhythmia group) of ventricular arrhythmias. Immediately after 15 min occlusion, myocardial samples were taken from the normal and reperfused areas to measure CoQ10 content of myocardium. Heart mitochondria were prepared after 5 min of reperfusion from both areas. Arrhythmias appeared in 12 of 38 dogs in the control group (32%), two of 24 dogs in the CoQ10-5 mg group (8%) and none of 15 dogs in the CoQ10-15 mg group (0%). Premedication with CoQ10 increased tissue CoQ10 content in a dose-dependent manner. In the CoQ10-5 mg group, the increase in CoQ10 content of dogs with reperfusion arrhythmias was relatively less than that of dogs without reperfusion arrhythmias. In each group, mitochondrial function was decreased in the arrhythmia group compared to that of the non-arrhythmia group. The increase in free fatty acid (FFA) content and the decrease in phospholipid content were also observed in mitochondria from the reperfused area of each arrhythmia group. The increase in FFA and mitochondrial dysfunction were induced by the incubation of mitochondria in vitro with phospholipase (PLase) A2 or PLase C, and protected by the addition of CoQ10. These results suggest that PLase plays an important role in the development of mitochondrial damage associated with reperfusion.