Mitochondrial DNA Medicine

2007 ◽  
Vol 27 (1-3) ◽  
pp. 5-9 ◽  
Author(s):  
Salvatore DiMauro
Keyword(s):  
Mitochondrial Dna ◽  
Protein Synthesis ◽  
Mitochondrial Protein ◽  
Point Mutations ◽  
Specific Protein ◽  
Mitochondrial Protein Synthesis ◽  
Mitochondrial Genetics ◽  
Protein Coding ◽  
Protein Coding Genes ◽  
Mitochondrial Medicine

The small, maternally inherited mitochondrial DNA (mtDNA) has turned out to be a hotbed of pathogenic mutations: 15 years into the era of ‘mitochondrial medicine’, over 150 pathogenic point mutations and countless rearrangements have been associated with a variety of multisystemic or tissue-specific human diseases. MtDNA-related disorders can be divided into two major groups: those due to mutations in genes affecting mitochondrial protein synthesis in toto and those due to mutations in specific protein-coding genes. Here we review the mitochondrial genetics and the clinical features of the mtDNA-related diseases.

scholarly journals Mitochondrial nucleoids maintain genetic autonomy but allow for functional complementation

2008 ◽  
Vol 181 (7) ◽  
pp. 1117-1128 ◽  
Author(s):  
Robert W. Gilkerson ◽  
Eric A. Schon ◽  
Evelyn Hernandez ◽  
Mercy M. Davidson
Keyword(s):  
Mitochondrial Dna ◽  
Protein Synthesis ◽  
Molecular Mechanism ◽  
Cell Lines ◽  
Mitochondrial Protein ◽  
Functional Complementation ◽  
Mitochondrial Protein Synthesis ◽  
Protein Assemblies ◽  
Mtdna Mutations ◽  
Mitochondrial Nucleoids

Mitochondrial DNA (mtDNA) is packaged into DNA-protein assemblies called nucleoids, but the mode of mtDNA propagation via the nucleoid remains controversial. Two mechanisms have been proposed: nucleoids may consistently maintain their mtDNA content faithfully, or nucleoids may exchange mtDNAs dynamically. To test these models directly, two cell lines were fused, each homoplasmic for a partially deleted mtDNA in which the deletions were nonoverlapping and each deficient in mitochondrial protein synthesis, thus allowing the first unequivocal visualization of two mtDNAs at the nucleoid level. The two mtDNAs transcomplemented to restore mitochondrial protein synthesis but were consistently maintained in discrete nucleoids that did not intermix stably. These results indicate that mitochondrial nucleoids tightly regulate their genetic content rather than freely exchanging mtDNAs. This genetic autonomy provides a molecular mechanism to explain patterns of mitochondrial genetic inheritance, in addition to facilitating therapeutic methods to eliminate deleterious mtDNA mutations.

scholarly journals In vitro genetic transfer of protein synthesis and respiration defects to mitochondrial DNA-less cells with myopathy-patient mitochondria.

1991 ◽  
Vol 11 (4) ◽  
pp. 2236-2244 ◽  
Author(s):  
A Chomyn ◽  
G Meola ◽  
N Bresolin ◽  
S T Lai ◽  
G Scarlato ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Protein Synthesis ◽  
Human Cell ◽  
Mitochondrial Myopathy ◽  
Mitochondrial Protein ◽  
Human Cell Lines ◽  
Mitochondrial Protein Synthesis ◽  
Direct Link ◽  
Genetic Transfer

A severe mitochondrial protein synthesis defect in myoblasts from a patient with mitochondrial myopathy was transferred with myoblast mitochondria into two genetically unrelated mitochondrial DNA (mtDNA)-less human cell lines, pointing to an mtDNA alteration as being responsible and sufficient for causing the disease. The transfer of the defect correlated with marked deficiencies in respiration and cytochrome c oxidase activity of the transformants and the presence in their mitochondria of mtDNA carrying a tRNA(Lys) mutation. Furthermore, apparently complete segregation of the defective genotype and phenotype was observed in the transformants derived from the heterogeneous proband myoblast population, suggesting that the mtDNA heteroplasmy in this population was to a large extent intercellular. The present work thus establishes a direct link between mtDNA alteration and a biochemical defect.

scholarly journals Phylogeny of water birds inferred from mitochondrial DNA sequences of nine protein coding genes

2014 ◽  
Author(s):  
Tsendsesmee Lkhagvajav Treutlein ◽  
Javier Gonzalez ◽  
Michael Wink
Keyword(s):  
Mitochondrial Dna ◽  
Dna Sequences ◽  
Mitochondrial Protein ◽  
Sister Relationship ◽  
Protein Coding ◽  
Water Bird ◽  
Protein Coding Genes ◽  
Reconstruction Methods ◽  
Mtdna Sequence ◽  
Water Birds

Background: The phylogeny of birds which are adapted to aquatic environments is controversial because of convergent evolution. Methods: To understand water bird evolution in more detail, we sequenced the majority of mitochondrial protein coding genes (6699 nucleotides in length) of 14 water birds, and reconstructed their phylogeny in the context of other taxa across the whole class of birds for which complete mitochondrial DNA (mtDNA) sequences were available. Results: The water bird clade, as defined by Hackett et al. (2008) based on nuclear DNA (ncDNA) sequences, was also found in our study by Bayesian Inference (BI) and Maximum Likelihood (ML) analyses. In both reconstruction methods, genera belonging to the same family generally clustered together with moderate to high statistical support. Above the family level, we identified three monophyletic groups: one clade consisting of Procellariidae, Hydrobatidae and Diomedeidae, and a second clade consisting of Sulidae, Anhingidae and Phalacrocoracidae, and a third clade consisting of Ardeidae and Threskiornithidae. Discussion: Based on our mtDNA sequence data, we recovered a robust direct sister relationship between Ardeidae and Threskiornithidae for the first time for mtDNA. Our comprehensive phylogenetic reconstructions contribute to the knowledge of higher level relationships within the water birds and provide evolutionary hypotheses for further studies.

scholarly journals MITOCHONDRIAL PROTEIN SYNTHESIS IN HELA CELLS

1974 ◽  
Vol 60 (3) ◽  
pp. 755-763 ◽  
Author(s):  
Jonas B. Galper
Keyword(s):  
Protein Synthesis ◽  
Ethidium Bromide ◽  
Mitochondrial Protein ◽  
Specific Protein ◽  
Mitochondrial Proteins ◽  
Mitochondrial Protein Synthesis ◽  
Initiator Trna ◽  
Low Concentrations ◽  
Separate Protein

HeLa cell mitochondrial proteins have been shown to be the products of two separate protein-synthesizing systems; one, the general cellular mechanism, sensitive to inhibition by cycloheximide, the other, a specific mitochondrial system subject to inhibition by low concentrations of chloramphenicol (Galper, J. B., and J. E. Darnell. 1971. J. Mol. Biol 57:363). Preliminary data have suggested that a mitochondrial N-formyl-methionyl-tRNA (f-Met-tRNA) might be the initiator tRNA in the latter (Galper, J. B., and J. E. Darnell. 1969. Biochem. Biophys. Res. Commun. 34:205; 1971. J. Mol. Biol. 57:363). It is demonstrated here that the synthesis of these endogenous mitochondrial proteins is also subject to inhibition by ethidium bromide and decays with a half-life of 1½–2 h in cultures incubated with low concentrations of this dye. The role of formylated f-Met-tRNA as the initiator tRNA in the synthesis of mitochondrial proteins is supported by data from several experiments. The rates of ethidium bromide inhibition of both the charging of f-Met-tRNA and of the synthesis of mitochondrial proteins are strikingly similar. Inhibition by aminopterin of the formylation of f-Met-tRNA greatly depresses the rate of mitochondrial-specific protein synthesis. In the absence of the synthesis of these proteins, respiration, the levels of cytochromes a–a3 and b, and the number of mitochondrial cristae are decreased. The implications of these findings as they relate to mitochondrial biogenesis are discussed.

scholarly journals Signatures of Adaptation in Mitochondrial Genomes of Palearctic Subterranean Voles (Arvicolinae, Rodentia)

Genes ◽  
2021 ◽  
Vol 12 (12) ◽  
pp. 1945
Author(s):  
Olga Bondareva ◽  
Evgeny Genelt-Yanovskiy ◽  
Tatyana Petrova ◽  
Semen Bodrov ◽  
Antonina Smorkatcheva ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Protein ◽  
Comparative Sequence Analysis ◽  
Selection Signatures ◽  
Subterranean Rodent ◽  
Protein Coding ◽  
Protein Coding Genes ◽  
Codon Substitution ◽  
Vole Species ◽  
The Common

This study evaluates signatures of selection in the evolution of the mitochondrial DNA of voles, subfamily Arvicolinae, during the colonization of subterranean environments. The comparative sequence analysis of mitochondrial protein-coding genes of eight subterranean vole species (Prometheomys schaposchnikowi, three species of the genus Ellobius: Ellobius talpinus, Ellobius fuscocapillus and Ellobius lutescens, two species of the genus Terricola: Terricola subterraneus and Terricola daghestanicus, Lasiopodomys mandarinus, and Hyperacrius fertilis) and their closest aboveground relatives was applied using codon-substitution models. The highest number of selection signatures was detected in genes ATP8 and CYTB. The relaxation of selection was observed in most mitochondrial DNA protein-coding genes for subterranean species. The largest amount of relaxed genes is discovered in mole voles (genus Ellobius). The number of selection signatures was found to be independent of the evolutionary age of the lineage but fits the degree of specialization to the subterranean niche. The common trends of selective pressures were observed among the evolutionary ancient and highly specialized subterranean rodent families and phylogenetically young lineages of voles. It suggests that the signatures of adaptation in individual mitochondrial protein-coding genes associated with the colonization of the subterranean niche may appear within a rather short evolutionary timespan.

scholarly journals Mitonuclear Interactions in the Maintenance of Mitochondrial Integrity

Life ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 173
Author(s):  
Panagiotis Karakaidos ◽  
Theodoros Rampias
Keyword(s):  
Mitochondrial Dna ◽  
Protein Synthesis ◽  
Mitochondrial Genome ◽  
Aging Process ◽  
Mitochondrial Protein ◽  
Eukaryotic Cells ◽  
Mitochondrial Protein Synthesis ◽  
Respiratory Chain Complexes ◽  
Chain Complexes ◽  
Insight Into

In eukaryotic cells, mitochondria originated in an α-proteobacterial endosymbiont. Although these organelles harbor their own genome, the large majority of genes, originally encoded in the endosymbiont, were either lost or transferred to the nucleus. As a consequence, mitochondria have become semi-autonomous and most of their processes require the import of nuclear-encoded components to be functional. Therefore, the mitochondrial-specific translation has evolved to be coordinated by mitonuclear interactions to respond to the energetic demands of the cell, acquiring unique and mosaic features. However, mitochondrial-DNA-encoded genes are essential for the assembly of the respiratory chain complexes. Impaired mitochondrial function due to oxidative damage and mutations has been associated with numerous human pathologies, the aging process, and cancer. In this review, we highlight the unique features of mitochondrial protein synthesis and provide a comprehensive insight into the mitonuclear crosstalk and its co-evolution, as well as the vulnerabilities of the animal mitochondrial genome.

scholarly journals In vitro genetic transfer of protein synthesis and respiration defects to mitochondrial DNA-less cells with myopathy-patient mitochondria

1991 ◽  
Vol 11 (4) ◽  
pp. 2236-2244
Author(s):  
A Chomyn ◽  
G Meola ◽  
N Bresolin ◽  
S T Lai ◽  
G Scarlato ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Protein Synthesis ◽  
Human Cell ◽  
Mitochondrial Myopathy ◽  
Mitochondrial Protein ◽  
Human Cell Lines ◽  
Mitochondrial Protein Synthesis ◽  
Direct Link ◽  
Genetic Transfer

A severe mitochondrial protein synthesis defect in myoblasts from a patient with mitochondrial myopathy was transferred with myoblast mitochondria into two genetically unrelated mitochondrial DNA (mtDNA)-less human cell lines, pointing to an mtDNA alteration as being responsible and sufficient for causing the disease. The transfer of the defect correlated with marked deficiencies in respiration and cytochrome c oxidase activity of the transformants and the presence in their mitochondria of mtDNA carrying a tRNA(Lys) mutation. Furthermore, apparently complete segregation of the defective genotype and phenotype was observed in the transformants derived from the heterogeneous proband myoblast population, suggesting that the mtDNA heteroplasmy in this population was to a large extent intercellular. The present work thus establishes a direct link between mtDNA alteration and a biochemical defect.

scholarly journals Reversible Inhibition of Mitochondrial Protein Synthesis during Linezolid-Related Hyperlactatemia

2006 ◽  
Vol 51 (3) ◽  
pp. 962-967 ◽  
Author(s):  
Glòria Garrabou ◽  
Alejandro Soriano ◽  
Sònia López ◽  
Jordi P. Guallar ◽  
Marta Giralt ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Protein Synthesis ◽  
Mononuclear Cells ◽  
Intact Cell ◽  
Mitochondrial Protein ◽  
Mitochondrial Rna ◽  
Mitochondrial Protein Synthesis ◽  
Peripheral Blood Mononuclear ◽  
Mitochondrial Mass ◽  
Clinical Recovery

ABSTRACT The objective of the present study was to determine the mitochondrial toxicity mechanisms of linezolid-related hyperlactatemia. Five patients on a long-term schedule of linezolid treatment were studied during the acute phase of hyperlactatemia and after clinical recovery and lactate normalization following linezolid withdrawal. Mitochondrial studies were performed with peripheral blood mononuclear cells and consisted of measurement of mitochondrial mass, mitochondrial protein synthesis homeostasis (cytochrome c oxidase [COX] activity, COX-II subunit expression, COX-II mRNA abundance, and mitochondrial DNA [mtDNA] content), and overall mitochondrial function (mitochondrial membrane potential and intact-cell oxidative capacity). During linezolid-induced hyperlactatemia, we found extremely reduced protein expression (16% of the remaining content compared to control values [100%], P < 0.001) for the mitochondrially coded, transcribed, and translated COX-II subunit. Accordingly, COX activity was also found to be decreased (51% of the remaining activity, P < 0.05). These reductions were observed despite the numbers of COX-II mitochondrial RNA transcripts being abnormally increased (297%, P = 0.10 [not significant]) and the mitochondrial DNA content remaining stable. These abnormalities persisted even after the correction for mitochondrial mass, which was mildly decreased during the hyperlactatemic phase. Most of the mitochondrial abnormalities returned to control ranges after linezolid withdrawal, lactate normalization, and clinical recovery. Linezolid inhibits mitochondrial protein synthesis, leading to decreased mitochondrial enzymatic activity, which causes linezolid-related hyperlactatemia, which resolves upon discontinuation of linezolid treatment.

scholarly journals Phylogeny of water birds inferred from mitochondrial DNA sequences of nine protein coding genes

2014 ◽  
Author(s):  
Tsendsesmee Lkhagvajav Treutlein ◽  
Javier Gonzalez ◽  
Michael Wink
Keyword(s):  
Mitochondrial Dna ◽  
Dna Sequences ◽  
Mitochondrial Protein ◽  
Sister Relationship ◽  
Protein Coding ◽  
Water Bird ◽  
Protein Coding Genes ◽  
Reconstruction Methods ◽  
Mtdna Sequence ◽  
Water Birds

Background: The phylogeny of birds which are adapted to aquatic environments is controversial because of convergent evolution. Methods: To understand water bird evolution in more detail, we sequenced the majority of mitochondrial protein coding genes (6699 nucleotides in length) of 14 water birds, and reconstructed their phylogeny in the context of other taxa across the whole class of birds for which complete mitochondrial DNA (mtDNA) sequences were available. Results: The water bird clade, as defined by Hackett et al. (2008) based on nuclear DNA (ncDNA) sequences, was also found in our study by Bayesian Inference (BI) and Maximum Likelihood (ML) analyses. In both reconstruction methods, genera belonging to the same family generally clustered together with moderate to high statistical support. Above the family level, we identified three monophyletic groups: one clade consisting of Procellariidae, Hydrobatidae and Diomedeidae, and a second clade consisting of Sulidae, Anhingidae and Phalacrocoracidae, and a third clade consisting of Ardeidae and Threskiornithidae. Discussion: Based on our mtDNA sequence data, we recovered a robust direct sister relationship between Ardeidae and Threskiornithidae for the first time for mtDNA. Our comprehensive phylogenetic reconstructions contribute to the knowledge of higher level relationships within the water birds and provide evolutionary hypotheses for further studies.

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