BBA - General Subjects (v.1820, #5)

Biochemistry of mitochondria, life and intervention 2010 by Yasutoshi Koga; Masashi Tanaka; Shigeo Ohta; Yau-Huei Wei (551-552).

A mitochondrial etiology of Alzheimer and Parkinson disease by Pinar Coskun; Joanne Wyrembak; Samual E. Schriner; Hsiao-Wen Chen; Christine Marciniack; Frank LaFerla; Douglas C. Wallace (553-564).
The genetics and pathophysiology of Alzheimer Disease (AD) and Parkinson Disease (PD) appears complex. However, mitochondrial dysfunction is a common observation in these and other neurodegenerative diseases.We argue that the available data on AD and PD can be incorporated into a single integrated paradigm based on mitochondrial genetics and pathophysiology.Rare chromosomal cases of AD and PD can be interpreted as affecting mitochondrial function, quality control, and mitochondrial DNA (mtDNA) integrity. mtDNA lineages, haplogroups, such haplogroup H5a which harbors the mtDNA tRNAGln A8336G variant, are important risk factors for AD and PD. Somatic mtDNA mutations are elevated in AD, PD, and Down Syndrome and Dementia (DSAD) both in brains and also systemically. AD, DS, and DSAD brains also have reduced mtDNA ND6 mRNA levels, altered mtDNA copy number, and perturbed Aβ metabolism. Classical AD genetic changes incorporated into the 3XTg-AD (APP, Tau, PS1) mouse result in reduced forebrain size, life-long reduced mitochondrial respiration in 3XTg-AD males, and initially elevated respiration and complex I and IV activities in 3XTg-AD females which markedly declines with age.Therefore, mitochondrial dysfunction provides a unifying genetic and pathophysiology explanation for AD, PD, and other neurodegenerative diseases. This article is part of a Special Issue entitled Biochemistry of Mitochondria.► We reviewed mitochondrial involvement in AD and PD pathophysiology and presented unpublished evidence for mitochondrial defect in AD animal model and PD patients. ► The important risk factors as certain mtDNA haplotypes in AD and PD was discussed. ► Somatic mtDNA mutation accumulation differences in AD and DSAD compared to age matched controls revisited and unpublished data presented on PD. ► Novel sex dependent decline in mitochondrial bioenergetics were presented in 3xTg-AD model throughout the life span. ► Hence mitochondrial dysfunction provides rational explanation to understand neurodegenerative diseases’ pathophysiology.
Keywords: Alzheimer Disease; Parkinson Disease; Mitochondria; mtDNA; 3XTg-AD Mouse; Oxidative phosphorylation;

The role of TFAM-associated proteins in mitochondrial RNA metabolism by Takeshi Uchiumi; Dongchon Kang (565-570).
Mammalian mitochondrial DNA (mtDNA) takes on a higher structure called the nucleoid or mitochromosome, which corresponds to that of nuclear DNA. Mitochondrial transcription factor A (TFAM), which was cloned as a transcription factor for mitochondrial DNA, is critical for forming this higher structure and for maintenance of mtDNA.To investigate the functional aspects of the nucleoid, we have identified many RNA-binding proteins to be candidate TFAM interactors, including ERAL1 and p32.In this review, we would like to describe that ERAL1 binds to the mitochondrial rRNA component of the ribosomal small subunit and is an important constituent of this subunit. p32, which is involved in mitochondrial translation, may be a novel marker of clinical progression in prostate cancer. Here we describe these proteins, all of which are involved in translation within the mitochondrial matrix.This review highlights the results from the mitochondrial nucleoid research in organic biochemistry. This article is part of a Special Issue entitled Biochemistry of Mitochondria.► TFAM is a component of mitochondrial nucleoids. ► ERAL1 is an assembly factor in mitochondrial ribosome. ► p32 might be an independent predictive factor.
Keywords: Mitochondrial DNA; Nucleoid; TFAM; Mitochondrial translation; Prostate cancer;

The self-renewal ability and pluripotent differentiation potential of stem cells hold great promise for regenerative medicine. Many studies focus on the lineage-specific differentiation and expansion of stem cells, but little is known about the regulation of glycolysis and mitochondrial biogenesis and function during these processes. Recent studies have demonstrated a strong correlation between cellular metabolism and the pluripotency and differentiation potential of stem cells, which indicates the importance of bioenergetic function in the regulation of stem cell physiology.We summarize recent findings in the control of stem cell competence through the regulation of bioenergetic function in embryonic, hematopoietic, mesenchymal, and induced pluripotent stem cells, and discuss the up-to-date understanding of the molecular mechanisms involved in these biological processes.It is believed that the metabolic signatures are highly correlated with the stemness status (high glycolytic flux) and differentiation potential (mitochondrial function) of stem cells. Besides, mitochondrial rejuvenation has been observed to participate in the reprogramming process.Understanding the metabolic regulation of stem cells will have great value in the characterization and isolation of stem cells with better differentiation potential. It also provides novel strategies of metabolic manipulation to increase the efficiency of cellular reprogramming. This article is part of a Special Issue entitled Biochemistry of Mitochondria, Life and Intervention 2010.► We summarize recent findings in the metabolic control of stem cell competence. ► Mitochondrial activity is highly associated with ESC pluripotency. ► Mitochondrial activity and ROS signaling are important for HSC self-renewal. ► Mitochondrial activity and ROS scavenging are crucial for MSC differentiation. ►Mitochondria undergo rejuvenation during cellular reprogramming.
Keywords: Stem cells; Pluripotency; Cell differentiation; Cellular reprogramming; Mitochondria; Metabolic shift;

Mitochondrial dysfunction is a prominent feature of neurodegenerative diseases including Parkinson's disease (PD), in which insulin signaling pathway may also be implicated because 50–80% of PD patients exhibited metabolic syndrome and insulin resistance. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its toxic metabolite, 1-methyl-4-phenyl-2,3-dihydropyridinium ion (MPP+), inhibit complex I in mitochondrial respiratory chain and are used widely to construct the PD models. But the precise molecular link between mitochondrial damage and insulin signaling remains unclear.Using cell-based mitochondrial activity profiling system, we systemically demonstrated that MPP+ suppressed mitochondrial activity and mitochondrial gene expressions mediated by nuclear respiratory factor-1 (NRF-1) and mitochondrial transcription factor A (TFAM) in SH-SY5Y cells. MPP+ fragmented mitochondrial networks and repressed phosphorylation of AKT. Similarly, the expressions of mitochondrial genes and tyrosine hydroxylase and AKT phosphorylation were reduced in substantia nigra and striatum of MPTP-injected mice. Transient transfection of TFAM, NRF-1, or myr-AKT reversed all aspects of the MPP+-mediated changes.Mitochondrial activation by TFAM, NRF-1, and myr-AKT abrogated MPP+-mediated damages on mitochondria and insulin signaling, leading to recovery of nigrostriatal neurodegeneration.We suggest that TFAM, NRF-1, and AKT may be the critical points of therapeutic intervention for PD. This article is part of a Special Issue entitled Biochemistry of Mitochondria.► MPP+ impaired mitochondrial activity and Akt signaling in neuronal cells. ► Overexpression of TFAM, NRF-1, and myr-AKT ameliorated the MPP+-induced damages. ► They may be critical targets for therapeutic intervention of parkinsonism.
Keywords: SH-SY5Y; MPP+; Insulin signaling; Mitochondrial dysfunction; Mouse;

Mitochondria are the major source of oxidative stress. Acute oxidative stress causes serious damage to tissues, and persistent oxidative stress is one of the causes of many common diseases, cancer and the aging process; however, there has been little success in developing an effective antioxidant with no side effect. We have reported that molecular hydrogen has potential as an effective antioxidant for medical applications [Ohsawa et al., Nat. Med. 13 (2007) 688–694].We review the recent progress toward therapeutic and preventive applications of hydrogen. Since we published the first paper in Nature Medicine, effects of hydrogen have been reported in more than 38 diseases, physiological states and clinical tests in leading biological/medical journals. Based on this cumulative knowledge, the beneficial biological effects of hydrogen have been confirmed. There are several ways to intake or consume hydrogen, including inhaling hydrogen gas, drinking hydrogen-dissolved water, taking a hydrogen bath, injecting hydrogen-dissolved saline, dropping hydrogen-dissolved saline into the eyes, and increasing the production of intestinal hydrogen by bacteria. Hydrogen has many advantages for therapeutic and preventive applications, and shows not only anti-oxidative stress effects, but also has various anti-inflammatory and anti-allergic effects. Preliminary clinical trials show that drinking hydrogen-dissolved water seems to improve the pathology of mitochondrial disorders.Hydrogen has biological benefits toward preventive and therapeutic applications; however, the molecular mechanisms underlying the marked effects of small amounts of hydrogen remain elusive.Hydrogen is a novel antioxidant with great potential for actual medical applications. This article is part of a Special Issue entitled Biochemistry of Mitochondria.► Mitochondrion is one of the major sources of oxidative stress. ► We found that H2 has potential as a very effective “novel” antioxidant. ► Recent many publications have confirmed beneficial biological effects of H2. ► H2 has many advantages as potential for therapeutic and preventive applications. ► Here, I review the recent progress toward the hydrogen medicine.
Keywords: Antioxidant; Hydrogen; Hydrogen medicine; Mitochondrion; Oxidative stress; Prevention;

Mitochondria and autophagy: Critical interplay between the two homeostats by Koji Okamoto; Noriko Kondo-Okamoto (595-600).
Mitochondria are dynamic organelles that frequently change their number, size, shape, and distribution in response to intra- and extracellular cues. After proliferated from pre-existing ones, fresh mitochondria enter constant cycles of fission and fusion that organize them into two distinct states — “individual state” and “network state”. When compromised with various injuries, solitary mitochondria are subjected to organelle degradation. This clearance pathway relies on autophagy, a self-eating process that plays key roles in manifold cell activities. Recent studies reveal that defects in autophagic degradation selective for mitochondria (mitophagy) are associated with neurodegenerative diseases, highlighting the physiological relevance to cellular functions.Here we review recent progress regarding a link between mitochondria and autophagy in yeast and multicellular eukaryotes. In particular, fundamental principles underlying mitophagy, and mitochondrial quality control are emphasized. Accumulating evidence also implicates nonselective autophagy in the management of mitochondrial fitness. Conversely, mitochondria are suggested to serve as signaling platforms vital for regulating autophagy. These interdependent relationships are likely to coordinate metabolic plasticity in the cell.Mitochondria and autophagy are elaborately linked homeostatic elements that act in response to changes in cellular environment such as energy, nutrient, and stress. How cells integrate these double membrane-bound systems still remains elusive.Interplay between mitochondria and autophagy seems to be evolutionarily conserved. Defects in one of these elements could simultaneously impair the other, resulting in risk increments for various human diseases. This article is part of a Special Issue entitled Biochemistry of Mitochondria.► Mitophagy and mitochondrial dynamics regulate mitochondrial quality control. ► Autophagy functions in maintenance of mitochondrial integrity. ► Mitochondrial structure and function play a key role in autophagy. ► Autophagy and the proteasome cooperatively act on mitochondria. ► Dysfunctions in mitochondria and autophagy synergistically potentiate disease risks.
Keywords: Biogenesis; Degradation; Fission; Fusion; Quality control; Reactive oxygen species;

Animal models of human mitochondrial DNA mutations by David A. Dunn; Matthew V. Cannon; Michael H. Irwin; Carl A. Pinkert (601-607).
Mutations in mitochondrial DNA (mtDNA) cause a variety of pathologic states in human patients. Development of animal models harboring mtDNA mutations is crucial to elucidating pathways of disease and as models for preclinical assessment of therapeutic interventions.This review covers the knowledge gained through animal models of mtDNA mutations and the strategies used to produce them. Animals derived from spontaneous mtDNA mutations, somatic cell nuclear transfer (SCNT), nuclear translocation of mitochondrial genes followed by mitochondrial protein targeting (allotopic expression), mutations in mitochondrial DNA polymerase gamma, direct microinjection of exogenous mitochondria, and cytoplasmic hybrid (cybrid) embryonic stem cells (ES cells) containing exogenous mitochondria (transmitochondrial cells) are considered.A wide range of strategies have been developed and utilized in attempts to mimic human mtDNA mutation in animal models. Use of these animals in research studies has shed light on mechanisms of pathogenesis in mitochondrial disorders, yet methods for engineering specific mtDNA sequences are still in development.Research animals containing mtDNA mutations are important for studies of the mechanisms of mitochondrial disease and are useful for the development of clinical therapies. This article is part of a Special Issue entitled Biochemistry of Mitochondria.► In vivo animal models of human mtDNA mutation based diseases are explored. ► Animal models harboring mtDNA modifications are derived using a variety of strategies. ► Transmitochondrial mice reflect both heteroplasmic and homoplasmic mtDNA mutations. ► Mitochondrial engineering in vivo and novel preclinical and therapeutic paradigms.
Keywords: Animal modeling; Mitochondria; Mitochondrial DNA (mtDNA); Mitochondrial disease; Transmitochondrial animal; Xenomitochondrial mouse;

Molecular pathology of MELAS and l-arginine effects by Yasutoshi Koga; Nataliya Povalko; Junko Nishioka; Koujyu Katayama; Shuichi Yatsuga; Toyojiro Matsuishi (608-614).
The pathogenic mechanism of stroke-like episodes seen in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) has not been clarified yet. About 80% of MELAS patients have an A3243G mutation in the mitochondrial tRNALeu(UUR) gene, which is the base change at position 14 in the consensus structure of tRNALeu(UUR) gene.This review aims to give an overview on the actual knowledge about the pathogenic mechanism of mitochondrial cytopathy at the molecular levels, the possible pathogenic mechanism of mitochondrial angiopathy to cause stroke-like episodes at the clinical and pathophysiological levels, and the proposed site of action of l-arginine therapy on MELAS.Molecular pathogenesis is mainly demonstrated using ρ0 cybrid system. The mutation creates the protein synthesis defects caused by 1) decreased life span of steady state amount of tRNALeu(UUR) molecules; 2) decreased ratio of aminoacyl-tRNALeu(UUR) versus uncharged tRNALeu(UUR) molecules; 3) the accumulation of aminoacylation with leucine without any misacylation; 4) accumulation of processing intermediates such as RNA 19, 5) wobble modification defects. All of these loss of function abnormalities are created by the threshold effects of cell or organ to the mitochondrial energy requirement when they establish the phenotype. Mitochondrial angiopathy demonstrated by muscle or brain pathology, as SSV (SDH strongly stained vessels), and by vascular physiology using FMD (flow mediated dilation). MELAS patients show decreased capacity of NO dependent vasodilation because of the low plasma levels of l-arginine and/or of respiratory chain dysfunction. Although the underlying mechanisms are not completely understood in stroke-like episodes in MELAS, l-arginine therapy improved endothelial dysfunction.Though the molecular pathogenesis of an A3243G or T3271C mutation of mitochondrial tRNALeu(UUR) gene has been clarified as a mitochondrial cytopathy, the underlying mechanisms of stroke-like episodes in MELAS are not completely understood. At this point, l-arginine therapy showed promise in treating of the stroke-like episodes in MELAS. This article is part of a Special Issue entitled Biochemistry of Mitochondria.Endothelial dysfunction is associated with MELAS, which demonstrated with segmental occlusions of small artery or arteriolen, SSVs in muscle and brain, decreased vasodilation by FMD physiologically. The mental stress, dehydration, fever and cold exposure are also very important factors to increase the risk of the stroke-like episodes in MELAS.Display Omitted► The pathogenic mechanism of stroke-like episodes in MELAS. ► molecular basis of mitochondrial cytoapthy. ► Clinical and pathophysiological evidences of mitochondrial angiopathy. ► The therapeutic action of l-arginine on stroke-like episodes in MELAS.
Keywords: Mitochondrial cytopathy; Translation; RNA 19; Angiopathy; Endothelial dysfunction; l-arginine;

In vivo functional brain imaging and a therapeutic trial of l-arginine in MELAS patients by Makoto Yoneda; Masamichi Ikawa; Kenichiro Arakawa; Takashi Kudo; Hirohiko Kimura; Yasuhisa Fujibayashi; Hidehiko Okazawa (615-618).
Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is the most common type of mitochondrial disease and is characterized by stroke-like episodes (SEs), myopathy, lactic acidosis, diabetes mellitus, hearing-loss and cardiomyopathy. The causal hypotheses for SEs in MELAS presented to date are angiopathy, cytopathy and neuronal hyperexcitability. L-arginine (Arg) has been applied for the therapy in MELAS patients.We will introduce novel in vivo functional brain imaging techniques such as MRI and PET, and discuss the pathogenesis of SEs in MELAS patients. We will further describe here our clinical experience with L-arg therapy and discuss the dual pharmaceutical effects of this drug on MELAS.Administration of L-arg to MELAS patients has been successful in reducing neurological symptoms due to acute strokes and preventing recurrences of SEs in the chronic phase. L-Arg has dual pharmaceutical effects on both angiopathy and cytopathy in MELAS. In vivo functional brain imaging promotes a better understanding of the pathogenesis and potential therapies for MELAS patients. This article is part of a Special Issue entitled Biochemistry of Mitochondria, Life and Intervention 2010.► Several novel in vivo functional brain imaging techniques were described. ► Such imaging techniques evaluated various conditions in MELAS patients. ► l-Arg has dual pharmaceutical effects on both angiopathy and cytopathy in MELAS.
Keywords: MELAS; Functional brain imaging; PET; MRI; l-arginine;

MELAS: A nationwide prospective cohort study of 96 patients in Japan by Shuichi Yatsuga; Nataliya Povalko; Junko Nishioka; Koju Katayama; Noriko Kakimoto; Toyojiro Matsuishi; Tatsuyuki Kakuma; Yasutoshi Koga (619-624).
A prospective cohort study of 96 Japanese patients with MELAS was followed between June 2003 and April 2008. Patients with MELAS were identified and enrolled based on questionnaires administered to neurologists in Japan. MELAS was defined using the Japanese diagnostic criteria for MELAS. Two follow-up questionnaires were administered to neurologists managing MELAS patients at an interval of 5 years.A prevalence of at least 0.58 (95% confidential interval (CI), 0.54–0.62)/100,000 was calculated for mitochondrial myopathy, whereas the prevalence of MELAS was 0.18 (95%CI, 0.02–0.34)/100,000 in the total population. MELAS patients were divided into two sub-groups: juvenile form and adult form. Stroke-like episodes, seizure and headache were the most frequent symptoms seen in both forms of MELAS. Short stature was significantly more frequent in the juvenile form, whereas hearing loss, cortical blindness and diabetes mellitus were significantly more frequent in the adult form. According to the Japanese mitochondrial disease rating scale, MELAS patients showed rapidly increasing scores (mean ± standard deviation, 12.8 ± 8.7) within 5 years from onset of the disease. According to a Kaplan–Meier analysis, the juvenile form was associated with a higher risk of death than the adult form (hazard ratio, 3.29; 95%CI, 1.32–8.20; p  = 0.0105).We confirmed that MELAS shows a rapid degenerative progression within a 5-year interval and that this occurs in both the juvenile and the adult forms of MELAS and follows different natural courses. This article is part of a Special Issue entitled: Biochemistry of Mitochondria.►The disease-based prevalence of MELAS is 0.18/100,000 in Japanese cohort study. ►MELAS has two subtypes, juvenile and adult, characterized by severity of disease. ►MELAS is a very severe disorder among mitochondrial myopathies. ►JMDRS is useful for evaluation of the disease progression in MELAS. ►Stroke-like episodes, headache and convulsion are the common symptoms in MELAS.
Keywords: Prevalence; MELAS; Cohort study; Natural course; Survival curve; Severity of disease;

CoQ10 deficiencies and MNGIE: Two treatable mitochondrial disorders by Michio Hirano; Caterina Garone; Catarina M. Quinzii (625-631).
Although causative mutations have been identified for numerous mitochondrial disorders, few disease-modifying treatments are available. Two examples of treatable mitochondrial disorders are coenzyme Q10 (CoQ10 or ubiquinone) deficiency and mitochondrial neurogastrointestinal encephalomyopathy (MNGIE).Here, we describe clinical and molecular features of CoQ10 deficiencies and MNGIE and explain how understanding their pathomechanisms have led to rationale therapies. Primary CoQ10 deficiencies, due to mutations in genes required for ubiquinone biosynthesis, and secondary deficiencies, caused by genetic defects not directly related to CoQ10 biosynthesis, often improve with CoQ10 supplementation. In vitro and in vivo studies of CoQ10 deficiencies have revealed biochemical alterations that may account for phenotypic differences among patients and variable responses to therapy. In contrast to the heterogeneous CoQ10 deficiencies, MNGIE is a single autosomal recessive disease due to mutations in the TYMP gene encoding thymidine phosphorylase (TP). In MNGIE, loss of TP activity causes toxic accumulations of the nucleosides thymidine and deoxyuridine that are incorporated by the mitochondrial pyrimidine salvage pathway and cause deoxynucleoside triphosphate pool imbalances, which, in turn cause mtDNA instability. Allogeneic hematopoetic stem cell transplantation to restore TP activity and eliminate toxic metabolites is a promising therapy for MNGIE.CoQ10 deficiencies and MNGIE demonstrate the feasibility of treating specific mitochondrial disorders through replacement of deficient metabolites or via elimination of excessive toxic molecules.Studies of CoQ10 deficiencies and MNGIE illustrate how understanding the pathogenic mechanisms of mitochondrial diseases can lead to meaningful therapies. This article is part of a Special Issue entitled: Biochemistry of Mitochondria, Life and Intervention 2010.►CoQ10 deficiencies can be primary (biosynthetic defects) or secondary (other causes). ►CoQ10 deficiencies often improve with high-dose CoQ10 supplements. ►MNGIE is caused by thymidine phosphorylase deficiency. ►MNGIE can improve after allogeneic hematopoetic stem cell transplantation.
Keywords: Coenzyme Q; Mitochondria; Mitochondrial DNA; MNGIE; Thymidine phosphorylase; Ubiquinone;

Pyruvate therapy for mitochondrial DNA depletion syndrome by Keiko Saito; Nobusuke Kimura; Nozomi Oda; Hideki Shimomura; Tomohiro Kumada; Tomoko Miyajima; Kei Murayama; Masashi Tanaka; Tatsuya Fujii (632-636).
Mitochondrial DNA depletion syndromes are a group of heterogeneous autosomal recessive disorders associated with a severe reduction in mitochondrial DNA in the affected tissues. Sodium pyruvate has been reported to have a therapeutic effect in mitochondrial diseases.We analyzed the effects of 0.5 g/kg of sodium pyruvate administered through a nasogastric tube in a one-year-old patient with myopathic mitochondrial DNA depletion syndrome. To evaluate the improvement, we used the Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) and manual muscle testing. As the improvement of motor functions in this severely disabled infant could not be comprehensively detected by NPMDS, we also observed the infant's ability to perform several tasks such as pouting, winking, and number of times she could tap a toy xylophone with a stick. Blood lactate and pyruvate levels were also monitored.After one month's treatment, the NPMDS score in section IV, the domain for the quality of life, improved from 17 to13. The infant became capable of raising her forearm, lower leg and wrist against gravity. The maximum number of times she could repeat each task increased and the movements became brisker and stronger. No significant change of the blood lactate level or lactate-to-pyruvate ratio, both of which were mildly increased at the initiation of the therapy, was observed despite the clinical improvement.Sodium pyruvate administered at 0.5 g/kg improved the muscle strength and the NPMDS score of an infant with myopathic mitochondrial DNA depletion syndrome.Sodium pyruvate may be effective for ameliorating the clinical manifestations of mitochondrial diseases. This article is part of a Special Issue entitled: Biochemistry of Mitochondria.► Pyruvate has been reported to improve energy metabolism in mitochondrial diseases. ► We examine the efficacy of pyruvate for mitochondrial DNA depletion syndrome (MDS). ► A patient with myopathic MDS showed improvement in muscle power. ► We conclude that pyruvate therapy is safe and effective for mitochondrial diseases.
Keywords: Pyruvate therapy; Mitochondrial DNA depletion syndrome; Mitochondrial diseases; Treatment; Lactate-to-pyruvate ratio; NAD+;

Prevention of mitochondrial disease inheritance by assisted reproductive technologies: Prospects and challenges by Akiko Yabuuchi; Zeki Beyhan; Noriko Kagawa; Chiemi Mori; Kenji Ezoe; Keiichi Kato; Fumihito Aono; Yuji Takehara; Osamu Kato (637-642).
Mitochondrial diseases are caused by the mutations in both nuclear and mitochondrial DNA (mtDNA) and the treatment options for patients who have mitochondrial disease are rather limited. Mitochondrial DNA is transmitted maternally and does not follow a Mendelian pattern of inheritance. Since reliable and predictable detection of mitochondrial disorders in embryos and oocytes is unattainable at present, an alternative approach to this problem has emerged as partial or complete replacement of mutated mtDNA with the wild-type mtDNA through embryo manipulations. Currently available methods to achieve this goal are germinal vesicle transfer (GVT), metaphase chromosome transfer (CT), pronuclear transfer (PNT) and ooplasmic transfer (OT).We summarize the state of the art regarding these technologies and discuss the implications of recent advances in the field for clinical practice.CT, PNT and GVT techniques hold promise to prevent transmission of mutant mtDNA through ARTs. However, it is clear that mtDNA heteroplasmy in oocytes, embryos and offspring produced by these methods remains as a legitimate concern.New approaches to eliminate transmission of mutant mtDNA certainly need to be explored in order to bring the promise of clinical application for the treatment of mitochondrial disorders. This article is part of a Special Issue entitled Biochemistry of Mitochondria, Life and Intervention 2010.► Recent studies for prevention of mitochondrial disease inheritance are digested. ► Exchanging of gamete cytoplasmic material is the way to prevent the inheritance. ► Currently available cell fusion methods cause mtDNA heteroplasmy. ► Further studies need to be performed carefully before the clinical application.
Keywords: Assisted reproductive technology; Mitochondrial disease; Mitochondrial DNA heteroplasmy; Germinal vesicle transfer;

Mitochondrial fumarate reductase as a target of chemotherapy: From parasites to cancer cells by Chika Sakai; Eriko Tomitsuka; Hiroyasu Esumi; Shigeharu Harada; Kiyoshi Kita (643-651).
Recent research on respiratory chain of the parasitic helminth, Ascaris suum has shown that the mitochondrial NADH-fumarate reductase system (fumarate respiration), which is composed of complex I (NADH–rhodoquinone reductase), rhodoquinone and complex II (rhodoquinol–fumarate reductase) plays an important role in the anaerobic energy metabolism of adult parasites inhabiting hosts. The enzymes in these parasite-specific pathways are potential target for chemotherapy. We isolated a novel compound, nafuredin, from Aspergillus niger, which inhibits NADH-fumarate reductase in helminth mitochondria at nM order. It competes for the quinone-binding site in complex I and shows high selective toxicity to the helminth enzyme. Moreover, nafuredin exerts anthelmintic activity against Haemonchus contortus in in vivo trials with sheep indicating that mitochondrial complex I is a promising target for chemotherapy. In addition to complex I, complex II is a good target because its catalytic direction is reverse of succinate–ubiquionone reductase in the host complex II. Furthermore, we found atpenin and flutolanil strongly and specifically inhibit mitochondrial complex II.Interestingly, fumarate respiration was found not only in the parasites but also in some types of human cancer cells. Analysis of the mitochondria from the cancer cells identified an anthelminthic as a specific inhibitor of the fumarate respiration. Role of isoforms of human complex II in the hypoxic condition of cancer cells and fetal tissues is a challenge. This article is part of a Special Issue entitled Biochemistry of Mitochondria, Life and Intervention 2010.► Fumarate respiration plays an important role in the energy metabolism of parasites. ► Fumarate respiration is found not only in the parasites but in human cancer cells. ► Fumarate respiration is a good target of chemotherapy for both parasites and cancer. ► Role of human complex II isoforms in hypoxic condition of cancer and fetal tissues.
Keywords: Mitochondrial fumarate respiration; Complex II; Hypoxia; Drug target; Ascaris suum; Type II flavoprotein subunit;

In only months-to-years a primary cancer can progress to an advanced phenotype that is metastatic and resistant to clinical treatments. As early as the 1900s, it was discovered that the progression of a cancer to the advanced phenotype is often associated with a shift in the metabolic profile of the disease from a state of respiration to anaerobic fermentation — a phenomenon denoted as the Warburg Effect.Reports in the literature strongly suggest that the Warburg Effect is generated as a response to a loss in the integrity of the sequence and/or copy number of the mitochondrial genome content within a cancer.Multiple studies regarding the progression of cancer indicate that mutation, and/or, a flux in the copy number, of the mitochondrial genome content can support the early development of a cancer, until; the mutational load and/or the reduction-to-depletion of the copy number of the mitochondrial genome content induces the progression of the disease to an advanced phenotype.Collectively, evidence has revealed that the human cell has incorporated the mitochondrial genome content into a cellular mechanism that, when pathologically actuated, can de(un)differentiate a cancer from the parental tissue of origin into an autonomous disease that disrupts the hierarchical structure-and-function of the human body. This article is part of a Special Issue entitled: Biochemistry of Mitochondria.►This review describes change in mitochondrial genome in cancer. ►Evidence shows that mitochondrial genome is predisposed to mutation in carcinogenesis. ►Then a burst of mutations occurred associated with advanced malignant phenotype.
Keywords: Mitochondria; Cancer; Mitochondrial DNA; Mutation; Depletion;

Role of advanced glycation end products (AGEs) and oxidative stress in vascular complications in diabetes by Sho-ichi Yamagishi; Sayaka Maeda; Takanori Matsui; Seiji Ueda; Kei Fukami; Seiya Okuda (663-671).
A non-enzymatic reaction between reducing sugars and amino groups of proteins, lipids and nucleic acids contributes to the aging of macromolecules, whose process has been known to progress at an accelerated rate under hyperglycemic and/or oxidative stress conditions. Over a course of days to weeks, early glycation products undergo further reactions such as rearrangements and dehydration to become irreversibly cross-linked, fluorescent protein derivatives termed advanced glycation end products (AGEs).In this paper, we review the role of AGE–oxidative stress axis and its therapeutic interventions in vascular complications in diabetes.AGEs elicit oxidative stress generation and subsequently cause inflammatory and thrombogenic reactions in various types of cells via interaction with a receptor for AGEs (RAGE), thereby being involved in vascular complications in diabetes. In addition, mitochondrial superoxide generation has been shown to play an important role in the formation and accumulation of AGEs under diabetic conditions. Further, we have recently found that a pathophysiological crosstalk between AGE–RAGE axis and renin–angiotensin system (RAS) could contribute to the progression of vascular damage in diabetes.These observations suggest that inhibition of AGE–RAGE–oxidative stress axis or blockade of its interaction with RAS is a novel therapeutic strategy for preventing vascular complications in diabetes.► AGEs elicit oxidative stress generation and subsequently cause inflammatory and thrombogenic reactions via interaction with a receptor for AGEs (RAGE). ► Mitochondrial superoxide generation plays an important role in the formation and accumulation of AGEs under diabetic conditions. ► A pathophysiological crosstalk between AGE–RAGE axis and renin–angiotensin system could contribute to vascular complications in diabetes. ► Inhibition of AGEs–RAGE–oxidative stress system is a therapeutic target for preventing vascular complications in diabetes.
Keywords: AGE; Oxidative stress; RAGE; Diabetic vascular complication;