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Mitochondrial dysfunction is an important cause of metabolic disorders of children and adults, with no effective therapy options. Recently, induction of mitochondrial biogenesis, by transgenic overexpression of PGC1-alpha [peroxisome proliferator-activated receptor (PPAR)-gamma coactivator 1-alpha], was reported to delay progression of early-onset cytochrome-c-oxidase (COX) deficiency in skeletal muscle of two mouse models: a muscle-specific knock-out of COX10 (COX10-mKO) and a constitutive knock-out of Surf1 (Surf1-KO). A pan-PPAR agonist, bezafibrate, could similarly delay myopathy progression in COX10-mKOs, but not in SURF1-KOs. We asked whether bezafibrate affected disease progression in late-onset adult-type mitochondrial myopathy mice. These 'Deletor mice' express a dominant patient mutation in Twinkle-helicase, leading to accumulation of multiple mtDNA deletions and subsequent progressive respiratory chain (RC) deficiency with COX-negative muscle fibers at 12 months of age. The primary and secondary molecular findings in Deletor mice mimic closely those in patients with Twinkle myopathy. We applied 0.5% bezafibrate diet to Deletors for 22 weeks, starting at disease manifestation, mimicking patient treatment after diagnosis. Bezafibrate delayed significantly the accumulation of COX-negative fibers and multiple mtDNA deletions. However, mitochondrial biogenesis was not induced: mitochondrial DNA copy number, transcript and RC protein amounts decreased in both Deletors and wild-type mice. Furthermore, bezafibrate induced severe lipid oxidation effects, with hepatomegaly and loss of adipose tissue, the mechanism involving lipid mobilization by high hepatic expression of FGF21 cytokine. However, as bezafibrate has been tolerated well by humans, the beneficial muscle findings in Deletor mice support consideration of bezafibrate trials on adult patients with mitochondrial myopathy.

Background 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. Scope of review 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. Major conclusions 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. General significance 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.

Background MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) (OMIM 540000 ) is the most dominant subtype of mitochondrial myopathy. The aim of this study was to determine the prevalence, natural course, and severity of MELAS. Methods 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. Results 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). Conclusions and General Significance 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.

Patients with type 1 diabetes mellitus (T1DM) sometimes have hepatomegaly and increased transaminase. This is usually due to non-alcoholic fatty liver disease (NAFLD) or, rarely, glycogenic hepatopathy (GH). A 13-year-old boy with NAFLD who was diagnosed with T1DM at 8 years of age, and a 13-year-old girl with GH who was found to have T1DM at 9 years of age were observed to have hepatomegaly and elevation of transaminase (aspartate aminotransferase [reference value, 12–30 IU/mL]/ alanine aminotransferase [reference value: 3–18 IU/mL]: 48/100 and 181/191, respectively). Their blood glucose levels had been poorly controlled for the last few years (HbA1c 11–12%). Lowdensity liver on computed tomography (CT) is usually seen in NAFLD, but sometimes, in early stage NAFLD, low-density liver is not seen on CT. Gradient dual-echo magnetic resonance imaging (MRI) can effectively discriminate glycogen from fat in the liver (Fig. 1). Therefore, we believe that gradient dual-echo MRI is a powerful tool to distinguish GH from NAFLD in T1DM with hepatomegaly and elevated transaminase.

The primary cause for strokelike episodes in young patients with MELAS (myopathy, encephalopathy, lactic acidosis, and strokelike episodes)—whether mitochondrial cytopathy, angiopathy, or both—remains controversial. Based on a hypothesis that strokelike episodes in MELAS are caused by segmental impairment of vasodilation in intracerebral arteries, we administered l-arginine to three patients with MELAS in the acute phase of stroke (within 1 hour of onset) and evaluated effects on clinical course, biochemical measurements, and functional cerebral hemodynamics according to 99mTc-ECD SPECT. ### Patients. Patient 1 was a 17-year-old woman referred to the hospital for periodic vomiting, hemiconvulsion, and short stature (below 2.7 SD). Patient 2 was an 18-year-old woman who was admitted to the hospital for generalized muscle weakness, periodic vomiting, hemiparesis, and short stature (below 1.5 SD). Patient 3 was a 15-year-old boy referred to our hospital for hemiblindness, hemiconvulsions, vomiting, and short stature (below 2.8 SD). All patients showed extensive calcification in the basal ganglia, lactic acidosis (3.8 to 5.6 mmol/L; normal range …

Objective To clarify the molecular basis of hypogonadotropic hypogonadism (HH). Design Genome-wide copy number analysis by array-based comparative genomic hybridization and systematic mutation screening of 29 known causative genes by next-generation sequencing, followed by in silico functional assessment and messenger RNA/DNA analyses of the mutants/variants. Setting Research institute. Patient(s) Fifty-eight patients with isolated HH (IHH), combined pituitary hormone deficiency (CPHD), and syndromic HH. Intervention(s) None. Main Outcome Measure(s) Frequency and character of molecular abnormalities. Result(s) Pathogenic defects were identified in 14 patients with various types of HH, although oligogenicity was not evident in this patient group. As rare abnormalities, we identified a submicroscopic deletion involving FGFR1 and an SOX3 polyalanine deletion in patients with IHH, and a WDR11 splice site mutation in a patient with CPHD. No disease-associated polymorphism was detected in the 58 patients. Conclusion(s) The present study provides further evidence that mutations and deletions in the known causative genes play a relatively minor role in the etiology of HH and that submicroscopic rearrangements encompassing FGFR1 can lead to IHH as a sole recognizable clinical feature. Furthermore, the results indicate for the first time that polyalanine deletions in SOX3 and mutations in WDR11 constitute rare genetic causes of IHH and CPHD, respectively.