scholarly journals Diabetic conditions induce intolerance to accumulation of pathogenic mitochondrial DNAs

2019 ◽  
Author(s):  
Emi Ogasawara ◽  
Shun Katada ◽  
Takayuki Mito ◽  
Jun-Ichi Hayashi ◽  
Kazuto Nakada
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Large Scale ◽  
Nuclear Genome ◽  
Mitochondrial Diseases ◽  
Pathogenic Mutation ◽  
Physiological Status ◽  
Trna Genes ◽  
Diabetic Mice

AbstractMarked accumulation of mitochondrial DNA (mtDNA) with a particular pathogenic mutation is necessary for the mutant mtDNA to express its pathogenicity as mitochondrial respiration defects. However, the nuclear genome background, or the physiological status, or both, might also be important for the pathogenic regulation of mutant mtDNAs, because most mitochondrial function is controlled by polypeptides encoded in the nuclear genome. To test this, we generated diabetic mice carrying pathogenic mtDNA with a large-scale deletion (ΔmtDNA) that loses six tRNA genes and seven structural genes essential for mitochondrial respiration. Compared with non-diabetic mice carrying ΔmtDNA, diabetic mice carrying ΔmtDNA showed a decrease in mitochondrial biogenesis regulated by nuclear-encoded genes, and mitochondrial respiration defects and the resultant mitochondrial disease phenotypes were induced even in the case of low loads of ΔmtDNA. In addition, diabetic culture conditions intensified the pathogenicity of human mtDNA with an A3243G point mutation in the tRNALue (UUR) gene. Our results indicated that the diabetic conditions are a modifier that exacerbates mitochondrial respiration defects due to mutant mtDNAs. The finding suggests the possibility that recovery from diabetic conditions might be an effective treatment strategy for some disorders involving both mutant mtDNAs and diabetic signs.Author SummaryIt has been reported that accumulation of pathogenic mutant mitochondrial DNA (mtDNA) and the resultant mitochondrial metabolic dysfunction are associated with a wide variety of disorders, such as mitochondrial diseases, diabetes, neuo-degenerative disorders, and cancers. Considering that most mitochondrial function is regulated by nuclear-genome-encoded polypeptides, it is very important to focus on cooperation between mutant mtDNA, nuclear genetic background, and vital conditions for understanding precise pathogeneses of mtDNA-mediated disorders. By using model cells and mice carrying pathogenic mtDNAs, we report here that diabetic conditions are a modifier for the pathogenic regulation of mutant mtDNAs. Because the onset and progression of diabetes are often associated with aging, our finding suggests that some age-associated disorders with mutant mtDNAs and diabetic complications might be induced partly by enhancement of the pathogenicity of mutant mtDNAs by diabetic conditions.

Loss of mitochondrial exo/endonuclease EXOG affects mitochondrial respiration and induces ROS-mediated cardiomyocyte hypertrophy

2015 ◽  
Vol 308 (2) ◽  
pp. C155-C163 ◽  
Author(s):  
Wardit Tigchelaar ◽  
Hongjuan Yu ◽  
Anne Margreet de Jong ◽  
Wiek H. van Gilst ◽  
Pim van der Harst ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Fold Increase ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Dna Integrity ◽  
Hypertrophic Response ◽  
Mitochondrial Ros ◽  
Mitochondrial Dna Repair

Recently, a locus at the mitochondrial exo/endonuclease EXOG gene, which has been implicated in mitochondrial DNA repair, was associated with cardiac function. The function of EXOG in cardiomyocytes is still elusive. Here we investigated the role of EXOG in mitochondrial function and hypertrophy in cardiomyocytes. Depletion of EXOG in primary neonatal rat ventricular cardiomyocytes (NRVCs) induced a marked increase in cardiomyocyte hypertrophy. Depletion of EXOG, however, did not result in loss of mitochondrial DNA integrity. Although EXOG depletion did not induce fetal gene expression and common hypertrophy pathways were not activated, a clear increase in ribosomal S6 phosphorylation was observed, which readily explains increased protein synthesis. With the use of a Seahorse flux analyzer, it was shown that the mitochondrial oxidative consumption rate (OCR) was increased 2.4-fold in EXOG-depleted NRVCs. Moreover, ATP-linked OCR was 5.2-fold higher. This increase was not explained by mitochondrial biogenesis or alterations in mitochondrial membrane potential. Western blotting confirmed normal levels of the oxidative phosphorylation (OXPHOS) complexes. The increased OCR was accompanied by a 5.4-fold increase in mitochondrial ROS levels. These increased ROS levels could be normalized with specific mitochondrial ROS scavengers (MitoTEMPO, mnSOD). Remarkably, scavenging of excess ROS strongly attenuated the hypertrophic response. In conclusion, loss of EXOG affects normal mitochondrial function resulting in increased mitochondrial respiration, excess ROS production, and cardiomyocyte hypertrophy.

scholarly journals Identification of Mitochondrial DNA (NUMTs) in the Nuclear Genome of Daphnia Magna

2020 ◽  
Author(s):  
Krzysztof Kowal ◽  
Angelika Tkaczyk ◽  
Mariusz Pierzchała ◽  
Adam Bownik ◽  
Brygida Ślaska
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Daphnia Magna ◽  
Sequence Homology ◽  
Nuclear Genome ◽  
Complete Information ◽  
Trna Genes ◽  
Entire Genome ◽  
Mtdna Sequence ◽  
D Loop

Abstract Background: This is the first study in which the Daphnia magna (D. magna) nuclear genome deposited in the GenBank data-base was analyzed for pseudogene sequences of mitochondrial origin. The first complete information about the genome of D. magna was published by Lee et al. in 2019. To date, there is no information about pseudogenes localized in the genome of D. magna . The aim of the present study was to identify NUMTs, their length, homology, and location for potential use in evolutionary studies and to check whether their occurrence causes co-amplification during mitochondrial genome analyses.Results: Bioinformatic analysis showed 1909 fragments of the mitochondrial genome of D. magna , of which 1630 fragments were located in ten linkage groups (LG) of the nuclear genome (nDNA). The most frequently occurring fragments of the mtDNA sequence in the nuclear genome included ND2 (115), ND3 (113), and TRNA-CYS (110)). However, the highest number of NUMTs was observed for the D-loop (147). 253 fragments showed 100% homology (from 16 to 46 bp) with mtDNA gene sequences. The sequence homology for TRNA-MET was 100% for all 6 NUMTs (from 16 to 18 bp). The overall length of NUMTs in the nDNA was 44.391 bp (from 16 to 182 bp), which accounted for 0.042% of the entire genome.Conclusions: The best-matched NUMTs covering more than 90% of the mtDNA gene sequence have been identified for the TRNA-ARG (95%), TRNA-GLU (97%), and TRNA-THR (95%) genes, and they may be included in the functional nuclear tRNA genes. Using the product of total DNA isolation in mtDNA studies, coamplification of nDNA fragments is unlikely in the case of amplification of the whole tRNA genes as well as fragments of other genes and the D-loop with a length exceeding 200 bp. It was observed that TRNA-MET fragments had the highest level of sequence homology, which means that they could be evolutionarily the youngest. The lowest degree of homology was found in the pseudogene derived from the mtDNA D-loop sequence. It may probably be the oldest element of mitochondrial DNA incorporated into the nuclear genome; however, further analysis is necessary.

scholarly journals Peripheral Benzodiazepine Binding Sites in Platelets of Patients Affected by Mitochondrial Diseases and Large Scale Mitochondrial DNA Rearrangements

2002 ◽  
Vol 8 (12) ◽  
pp. 841-846 ◽  
Author(s):  
Claudia Martini ◽  
Beatrice Chelli ◽  
Laura Betti ◽  
Marina Montali ◽  
Michelangelo Mancuso ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Binding Sites ◽  
Large Scale ◽  
Mitochondrial Diseases ◽  
Dna Rearrangements ◽  
Benzodiazepine Binding ◽  
Benzodiazepine Binding Sites

scholarly journals Expanding and validating the biomarkers for mitochondrial diseases

2020 ◽  
Vol 98 (10) ◽  
pp. 1467-1478
Author(s):  
Alessandra Maresca ◽  
◽  
Valentina Del Dotto ◽  
Martina Romagnoli ◽  
Chiara La Morgia ◽  
...  
Keyword(s):  
Metabolic Disorders ◽  
Nuclear Genome ◽  
Mitochondrial Diseases ◽  
Genetic Alterations ◽  
Fibroblast Growth Factor 21 ◽  
Trna Genes ◽  
The Novel ◽  
Longitudinal Assessment ◽  
Mitochondrial Translation ◽  
Monitoring Therapy

Abstract Mitochondrial diseases are highly heterogeneous metabolic disorders caused by genetic alterations in the mitochondrial DNA (mtDNA) or in the nuclear genome. In this study, we investigated a panel of blood biomarkers in a cohort of 123 mitochondrial patients, with prominent neurological and muscular manifestations. These biomarkers included creatine, fibroblast growth factor 21 (FGF21) and growth/differentiation factor 15 (GDF-15), and the novel cell free circulating-mtDNA (ccf-mtDNA). All biomarkers were significantly increased in the patient group. After stratification by the specific phenotypes, ccf-mtDNA was significantly increased in the Mitochondrial Encephalomyopathy Lactic Acidosis Stroke-like episodes syndrome (MELAS) group, and FGF21 and GDF-15 were significantly elevated in patients with MELAS and Myoclonic Epilepsy Ragged Red Fibers syndrome. On the contrary, in our cohort, creatine was not associated to a specific clinical phenotype. Longitudinal assessment in four MELAS patients showed increased levels of ccf-mtDNA in relation to acute events (stroke-like episodes/status epilepticus) or progression of neurodegeneration. Our results confirm the association of FGF21 and GDF-15 with mitochondrial translation defects due to tRNA mutations. Most notably, the novel ccf-mtDNA was strongly associated with MELAS and may be used for monitoring the disease course or to evaluate the efficacy of therapies, especially in the acute phase. Key messages • FGF21/GDF15 efficiently identifies mitochondrial diseases due to mutations in tRNA genes. • The novel ccf-mtDNA is associated with MELAS and increases during acute events. • Creatine only discriminates severe mitochondrial patients. • FGF21, GDF-15, and ccf-mtDNA are possibly useful for monitoring therapy efficacy.

A study of mitochondrial DNA mutations in peripheral lymphocytes in an aging cohort

2003 ◽  
Vol 31 (2) ◽  
pp. 444-446 ◽  
Author(s):  
B. Zhang ◽  
S. Ye ◽  
A.A. Sayer ◽  
S.R. Hammans ◽  
S. Adio ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Somatic Mutation ◽  
Large Scale ◽  
Nuclear Genome ◽  
Epidemiological Studies ◽  
Elderly Subjects ◽  
Long Pcr ◽  
Peripheral Lymphocytes ◽  
Wide Range

Somatic mutation in the mitochondrial genome occurs much more rapidly than in the nuclear genome and is a feature, possibly contributory, of the aging of cells and tissues. Identifying mitochondrial sequence changes in blood DNA of elderly subjects may provide a maker for the epigenetic changes of mitochondrial DNA known to occur in tissues with lower cellular turnover, and would also have implications for immunosenescence. No large-scale epidemiological studies have been reported previously. In this study we have established long-PCR banks of the mitochondrial genome from peripheral lymphocytes for an elderly cohort of 716 individuals with a range of measured aging phenotypes, and we have established assays for three widely reported mutations: the 4977 bp and 8048 bp deletions and point mutation A3243G. No individuals were identified with detectable heteroplasmy for these changes. Implications for tissue and population prevalence are discussed. The mitochondrial long-PCR DNA banks established will be useful for a wide range of studies of somatic mutation and of germline haplotypes in relation to aging.

scholarly journals Altered mitochondrial function in fibroblasts containing MELAS or MERRF mitochondrial DNA mutations

1996 ◽  
Vol 318 (2) ◽  
pp. 401-407 ◽  
Author(s):  
Andrew M JAMES ◽  
Yau-Huei WEI ◽  
Cheng-Yoong PANG ◽  
Michael P. MURPHY
Keyword(s):  
Mitochondrial Dna ◽  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Function ◽  
Mitochondrial Membrane ◽  
Trna Genes ◽  
Primary Fibroblast ◽  
Cultured Fibroblasts ◽  
Mitochondrial Dna Mutations ◽  
Dna Mutations

A number of human diseases are caused by inherited mitochondrial DNA mutations. Two of these diseases, MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) and MERRF (myoclonic epilepsy and ragged-red fibres), are commonly caused by point mutations to tRNA genes encoded by mitochondrial DNA. Here we report on how these mutations affect mitochondrial function in primary fibroblast cultures established from a MELAS patient containing an A to G mutation at nucleotide 3243 in the tRNALeu(UUR) gene and a MERRF patient containing an A to G mutation at nucleotide 8344 in the tRNALys gene. Both mitochondrial membrane potential and respiration rate were significantly decreased in digitonin-permeabilized MELAS and MERRF fibroblasts respiring on glutamate/malate. A similar decrease in mitochondrial membrane potential was found in intact MELAS and MERRF fibroblasts. The mitochondrial content of these cells, estimated by stereological analysis of electron micrographs and from measurement of mitochondrial marker enzymes, was similar in control, MELAS and MERRF cells. Therefore, in cultured fibroblasts, mutation of mitochondrial tRNA genes leads to assembly of bioenergetically incompetent mitochondria, not to an alteration in their amount. However, the cell volume occupied by secondary lysosomes and residual bodies in the MELAS and MERRF cells was greater than in control cells, suggesting increased mitochondrial degradation in these cells. In addition, fibroblasts containing mitochondrial DNA mutations were 3–4-fold larger than control fibroblasts. The implications of these findings for the pathology of mitochondrial diseases are discussed.

Effects of the cannabinoid CB1 antagonist rimonabant on hepatic mitochondrial function in rats fed a high-fat diet

2009 ◽  
Vol 297 (5) ◽  
pp. E1162-E1170 ◽  
Author(s):  
Mélissa Flamment ◽  
Naïg Gueguen ◽  
Céline Wetterwald ◽  
Gilles Simard ◽  
Yves Malthièry ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Atp Synthase ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
High Fat Diet ◽  
Cell Function ◽  
Citrate Synthase ◽  
Sprague Dawley ◽  
High Fat ◽  
Serum Triglycerides

The aim of this study was to investigate the effect of rimonabant treatment on hepatic mitochondrial function in rats fed a high-fat diet. Sprague-Dawley rats fed a high-fat diet (35% lard) for 13 wk were treated with rimonabant (10 mg·kg−1·day−1) during the last 3 wk and matched with pair-fed controls. Oxygen consumption with various substrates, mitochondrial enzyme activities on isolated liver mitochondria, and mitochondrial DNA quantity were determined. Body weight and fat mass were decreased in rats treated with rimonabant compared with pair-fed controls. Moreover, the serum adiponectin level was increased with rimonabant. Hepatic triglyceride content was increased, while serum triglycerides were decreased. An increase of mitochondrial respiration was observed in rats treated with rimonabant. The increase of mitochondrial respiration with palmitoyl-CoA compared with respiration with palmitoyl-l-carnitine stating that the entry of fatty acids into mitochondria via carnitine palmitoyltransferase I was increased in rats treated with rimonabant. Moreover, rimonabant treatment led to a reduction in the enzymatic activity of ATP synthase, whereas the quantity of mitochondrial DNA and the activity of citrate synthase remained unchanged. To summarize, rimonabant treatment leads to an improvement of hepatic mitochondrial function by increasing substrate oxidation and fatty acid entry into mitochondria for the β-oxidation pathway and by increasing proton leak. However, this increase of mitochondrial oxidation is regulated by a decrease of ATP synthase activity in order to have only ATP required for the cell function.

scholarly journals Leukocyte cytokine responses in adult patients with mitochondrial DNA defects

2021 ◽  
Author(s):  
Kalpita R Karan ◽  
Caroline Trumpff ◽  
Marissa Cross ◽  
Kristin M Englestad ◽  
Anna L Marsland ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Large Scale ◽  
Cytokine Production ◽  
Ex Vivo ◽  
Mitochondrial Diseases ◽  
Preliminary Evidence ◽  
Cytokine Responses ◽  
Mtdna Deletions ◽  
Immune Challenges

Patients with oxidative phosphorylation (OxPhos) defects causing mitochondrial diseases appear particularly vulnerable to infections. Although OxPhos defects modulate cytokine production in vitro and in animal models, little is known about how circulating leukocytes of patients with inherited mitochondrial DNA (mtDNA) defects respond to acute immune challenges. In a small cohort of healthy controls (n=21) and patients (n=12) with either the m.3243A>G mutation or single, large-scale mtDNA deletions, we examined: i) cytokine responses (IL-6, TNF-α, IL-1β) in response to acute lipopolysaccharide (LPS) exposure, and ii) sensitivity to the immunosuppressive effects of glucocorticoid signaling (dexamethasone) on cytokine production. In dose-response experiments to determine the half-maximal effective LPS concentration (EC50), relative to controls, leukocytes from patients with mtDNA deletions showed 174 -179% lower responses for IL-6 and IL-1β (pIL-6=0.031, pIL-1β=0.009). Moreover, IL-6 response to LPS in presence of GC was also blunted in cells from patients with mtDNA deletions (pIL-6=0.006), but not in leukocytes from patients with the m.3243A>G mutation. Overall, these ex vivo data provide preliminary evidence that some systemic OxPhos defects may compromise immune cytokine responses and glucocorticoid sensitivity. Further work in larger cohorts is needed to define the nature of immune dysregulation in patients with mitochondrial disease, and their potential implications for disease phenotypes.

Mitochondrial DNA-related Disorders

2007 ◽  
Vol 27 (1-3) ◽  
pp. 31-37 ◽  
Author(s):  
Michelangelo Mancuso ◽  
Massimiliano Filosto ◽  
Anna Choub ◽  
Marta Tentorio ◽  
Laura Broglio ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Genome ◽  
Respiratory Chain ◽  
Nuclear Genome ◽  
Mitochondrial Diseases ◽  
Mitochondrial Respiratory Chain ◽  
Mitochondrial Genetics ◽  
Respiratory Chain Deficiency ◽  
Clinical Syndromes ◽  
Clinical Pictures

Mitochondrial diseases are a group of disorders due to a mitochondrial respiratory chain deficiency. They may depend on mitochondrial genome (mtDNA-related disorders) as well as on a nuclear genome defect (nDNA-related disorders). mtDNA-related disorders encompass an increasing number of clinical pictures associated with more than 250 different provisional or confirmed pathogenic changes in mtDNA. Although some clinical syndromes are nosologically defined, most of the cases present with polymorphous phenotypes ranging from pure myopathy to multi-system involvement. Complexity of mitochondrial genetics is in part responsible for the extreme clinical intra- and inter-familial heterogeneity of this group of diseases. In this review, we briefly report an updated classification and overview the main clinical pictures of this class of diseases.

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