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Neurobiology of Aging May 2017Although mitochondrial dysfunction is a consistent feature of Alzheimer's disease in the brain and blood, the molecular mechanisms behind these phenomena are unknown....
Although mitochondrial dysfunction is a consistent feature of Alzheimer's disease in the brain and blood, the molecular mechanisms behind these phenomena are unknown. Here we have replicated our previous findings demonstrating reduced expression of nuclear-encoded oxidative phosphorylation (OXPHOS) subunits and subunits required for the translation of mitochondrial-encoded OXPHOS genes in blood from people with Alzheimer's disease and mild cognitive impairment. Interestingly this was accompanied by increased expression of some mitochondrial-encoded OXPHOS genes, namely those residing closest to the transcription start site of the polycistronic heavy chain mitochondrial transcript (MT-ND1, MT-ND2, MT-ATP6, MT-CO1, MT-CO2, MT-C03) and MT-ND6 transcribed from the light chain. Further we show that mitochondrial DNA copy number was unchanged suggesting no change in steady-state numbers of mitochondria. We suggest that an imbalance in nuclear and mitochondrial genome-encoded OXPHOS transcripts may drive a negative feedback loop reducing mitochondrial translation and compromising OXPHOS efficiency, which is likely to generate damaging reactive oxygen species.
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Biomarkers; Cognitive Dysfunction; Female; Gene Expression; Genes, Mitochondrial; Humans; Male; Mitochondria; Oxidative Phosphorylation; Reactive Oxygen Species; Transcription, Genetic
PubMed: 28208064
DOI: 10.1016/j.neurobiolaging.2016.12.029 -
MBio Apr 2013Uniparental inheritance of mitochondrial DNA is pervasive in nonisogamic higher eukaryotes during sexual reproduction, and postzygotic and/or prezygotic factors are...
UNLABELLED
Uniparental inheritance of mitochondrial DNA is pervasive in nonisogamic higher eukaryotes during sexual reproduction, and postzygotic and/or prezygotic factors are shown to be important in ensuring such an inheritance pattern. Although the fungus Cryptococcus neoformans undergoes sexual production with isogamic partners of opposite mating types a and α, most progeny derived from such mating events inherit the mitochondrial DNA (mtDNA) from the a parent. The homeodomain protein complex Sxi1α/Sxi2a, formed in the zygote after a-α cell fusion, was previously shown to play a role in this uniparental mtDNA inheritance. Here, we defined the timing of the establishment of the mtDNA inheritance pattern during the mating process and demonstrated a critical role in determining the mtDNA inheritance pattern by a prezygotic factor, Mat2. Mat2 is the key transcription factor that governs the pheromone sensing and response pathway, and it is critical for the early mating events that lead to cell fusion and zygote formation. We show that Mat2 governs mtDNA inheritance independently of the postzygotic factors Sxi1α/Sxi2a, and the cooperation between these prezygotic and postzygotic factors helps to achieve stricter uniparental mitochondrial inheritance in this eukaryotic microbe.
IMPORTANCE
Mitochondrial DNA is inherited uniparentally from the maternal parent in the majority of eukaryotes. Studies done on higher eukaryotes such as mammals have shown that the transmission of parental mitochondrial DNA is controlled at both the prefertilization and postfertilization stages to achieve strict uniparental inheritance. However, the molecular mechanisms underlying such uniparental mitochondrial inheritance have been investigated in detail mostly in anisogamic multicellular eukaryotes. Here, we show that in a simple isogamic microbe, Cryptococcus neoformans, the mitochondrial inheritance is controlled at the prezygotic level as well as the postzygotic level by regulators that are critical for sexual development. Furthermore, the cooperation between these two levels of control ensures stricter uniparental mitochondrial inheritance, echoing what has been observed in higher eukaryotes. Thus, the investigation of uniparental mitochondrial inheritance in this eukaryotic microbe could help advance our understanding of the convergent evolution of this widespread phenomenon in the eukaryotic domain.
Topics: Cryptococcus neoformans; DNA, Mitochondrial; Genes, Mating Type, Fungal; Genes, Mitochondrial; Time Factors
PubMed: 23611907
DOI: 10.1128/mBio.00112-13 -
Aging Cell Oct 2011Fluorescence loss in photobleaching experiments and analysis of mitochondrial function using superoxide and redox potential biosensors revealed that mitochondria within...
Fluorescence loss in photobleaching experiments and analysis of mitochondrial function using superoxide and redox potential biosensors revealed that mitochondria within individual yeast cells are physically and functionally distinct. Mitochondria that are retained in mother cells during yeast cell division have a significantly more oxidizing redox potential and higher superoxide levels compared to mitochondria in buds. Retention of mitochondria with more oxidizing redox potential in mother cells occurs to the same extent in young and older cells and can account for the age-associated decline in total cellular mitochondrial redox potential in yeast as they age from 0 to 5 generations. Deletion of Mmr1p, a member of the DSL1 family of tethering proteins that localizes to mitochondria at the bud tip and is required for normal mitochondrial inheritance, produces defects in mitochondrial quality control and heterogeneity in replicative lifespan (RLS). Long-lived mmr1Δ cells exhibit prolonged RLS, reduced mean generation times, more reducing mitochondrial redox potential and lower mitochondrial superoxide levels compared to wild-type cells. Short-lived mmr1Δ cells exhibit the opposite phenotypes. Moreover, short-lived cells give rise exclusively to short-lived cells, while the majority of daughters of long-lived cells are long lived. These findings support the model that the mitochondrial inheritance machinery promotes retention of lower-functioning mitochondria in mother cells and that this process contributes to both mother-daughter age asymmetry and age-associated declines in cellular fitness.
Topics: Cell Division; Fluorescence; Genes, Mitochondrial; Mitochondria; Mitochondrial Proteins; Mutation; Oxidation-Reduction; Photobleaching; Recombinant Fusion Proteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Silent Information Regulator Proteins, Saccharomyces cerevisiae; Sirtuin 2; Superoxides; Time Factors
PubMed: 21726403
DOI: 10.1111/j.1474-9726.2011.00731.x -
Nature Plants Nov 2023Fusion proteins derived from transcription activator-like effectors (TALEs) have emerged as genome editing tools for mitochondria. TALE nucleases (TALENs) have been...
Fusion proteins derived from transcription activator-like effectors (TALEs) have emerged as genome editing tools for mitochondria. TALE nucleases (TALENs) have been applied to delete chimaeric reading frames and duplicated (redundant) genes but produced complex genomic rearrangements due to the absence of non-homologous end-joining. Here we report the targeted deletion of a conserved mitochondrial gene, nad9, encoding a subunit of respiratory complex I. By generating a large number of TALEN-mediated mitochondrial deletion lines, we isolated, in addition to mutants with rearranged genomes, homochondriomic mutants harbouring clean nad9 deletions. Characterization of the knockout plants revealed impaired complex I biogenesis, male sterility and defects in leaf and flower development. We show that these defects can be restored by expressing a functional Nad9 protein from the nuclear genome, thus creating a synthetic cytoplasmic male sterility system. Our data (1) demonstrate the feasibility of using genome editing to study mitochondrial gene functions by reverse genetics, (2) highlight the role of complex I in plant development and (3) provide proof-of-concept for the construction of synthetic cytoplasmic male sterility systems for hybrid breeding by genome editing.
Topics: Gene Editing; Genes, Mitochondrial; Plant Breeding; Plants; Mitochondria; Genome, Plant
PubMed: 37814021
DOI: 10.1038/s41477-023-01538-2 -
Molecular Vision 2021Keratoconus (KC) is a corneal disorder characterized by corneal ectasia, progressive corneal thinning, and conical protrusion. This study aimed to elucidate the...
PURPOSE
Keratoconus (KC) is a corneal disorder characterized by corneal ectasia, progressive corneal thinning, and conical protrusion. This study aimed to elucidate the mitochondrial gene profile in Chinese patients with KC, analyze the mitochondrial haplogroup and heteroplasmy, and further explore the association between mitochondrial genes and KC.
METHODS
Mitochondrial sequencing was conducted on 100 patients with KC and 100 matched controls. Haplogroup analysis was conducted with logistic regression analysis. The heteroplasmy was analyzed with ANOVA (ANOVA) and Student test. Sequence kernel association tests (SKATs) were performed to analyze the association between mitochondrial genes and KC. Mtoolbox, Mitoclass.1, and APOGEE were used to estimate the impact of the identified variants in protein-coding genes. PON-mt-tRNA was used to annotate the impact of the variants in tRNA. RNAstructure was used to predict the secondary structures of native and mutated tRNAs.
RESULTS
We identified 689 variants in patients with KC and 725 variants in controls (with 308 variants shared by both). The mitochondrial haplogroups exhibited no statistically significant differences between the two groups. Based on the heteroplasmy analysis, the number of heteroplasmic variants in the complete mitochondrial genome, RNA coding regions, and noncoding regions were statistically significantly different in the KC cases and controls (p<0.05). The heteroplasmic levels of the m.16180_16182delAA, m.16182insC, and m.14569 G>C variants in the KC cases were statistically significantly higher than those in the controls (p<0.05). The SKAT analysis showed that the and genes were statistically significantly associated with KC (p<0.05). Among the nine variants of included in the SKAT analysis (m.9300G>A, m.9316T>C, m.9327A>G, m.9355A>G, m.9468A>G, m.9612G>A, m.9804G>A, m.9957G>A, and m.9966 G>A), m.9612G>A was predicted to be deleterious by Mtoolbox. The m.9316T>C, m.9327A>G, m.9355A>G, m.9612G>A, m.9804G>A, and m.9957G>A variants were predicted to be damaging by Mitoclass.1. The m.9355A>G and m.9804G>A variants were predicted to be pathogenic by APOGEE. All identified variants located in (m.12153C>T, m.12178C>T, and m.12192G>A) were predicted to be neutral by the PON-mt-tRNA website.
CONCLUSIONS
This study presents the mitochondrial gene profile of Chinese patients with KC and demonstrated that the and genes were associated with KC.
Topics: Adolescent; Asian People; China; DNA, Mitochondrial; Electron Transport Complex IV; Female; Genes, Mitochondrial; Genome, Mitochondrial; Humans; Keratoconus; Male; Mutation; RNA, Transfer, His; Young Adult
PubMed: 34012229
DOI: No ID Found -
Biochimica Et Biophysica Acta Dec 2009The cellular consequences of deficiencies of the mitochondrial OXPHOS system include a variety of direct and secondary changes in metabolite homeostasis, such as ROS,... (Review)
Review
The cellular consequences of deficiencies of the mitochondrial OXPHOS system include a variety of direct and secondary changes in metabolite homeostasis, such as ROS, Ca(2+), ADP/ATP, and NAD/NADH. The adaptive responses to these changes include the transcriptional responses of nuclear and mitochondrial genes that are mediated by these metabolites, control of the mitochondria permeability transition pore, and a great variety of secondary signalling elements. Among the transcriptional responses reported over more than a decade using material harboring mtDNA mutations, deletions, or depletions, nuclear and mitochondrial DNA OXPHOS genes have mostly been up-regulated. However, it is evident from the limited data in a variety of disease models that expression responses are highly diverse and inconsistent. In this article, the mechanisms and controlling elements of these transcriptional responses are reviewed. In addition, the elements that need to be evaluated, in order to gain an improved perspective of the manner in which OXPHOS genes respond and impact on mitochondrial disease expression, are highlighted.
Topics: Gene Expression; Genes, Mitochondrial; Humans; Mitochondrial Diseases; Oxidative Phosphorylation
PubMed: 19389473
DOI: 10.1016/j.bbadis.2009.04.003 -
PeerJ 2023Thoracotremata belong to the large group of "true" crabs (infraorder Brachyura), and they exhibit a wide range of physiological and morphological adaptations to living...
BACKGROUND
Thoracotremata belong to the large group of "true" crabs (infraorder Brachyura), and they exhibit a wide range of physiological and morphological adaptations to living in terrestrial, freshwater and marine habitats. Moreover, the clade comprises various symbiotic taxa (Aphanodactylidae, Cryptochiridae, Pinnotheridae, some Varunidae) that are specialised in living with invertebrate hosts, but the evolutionary history of these symbiotic crabs is still partially unresolved.
METHODS
Here we assembled and characterised the complete mitochondrial genomes (hereafter mitogenomes) of three gall crab species (Cryptochiridae): , and . A phylogenetic tree of the Thoracotremata was reconstructed using 13 protein-coding genes and two ribosomal RNA genes retrieved from three new gall crab mitogenomes and a further 72 available thoracotreme mitogenomes. Furthermore, we applied a comparative analysis to characterise mitochondrial gene order arrangement, and performed a selection analysis to test for selective pressure of the protein-coding genes in symbiotic Cryptochiridae, Pinnotheridae, and Varunidae ( and ).
RESULTS
The results of the phylogenetic reconstruction confirm the monophyly of Cryptochiridae, which clustered separately from the Pinnotheridae. The latter clustered at the base of the tree with robust branch values. The symbiotic varunids and clustered together in a clade with free-living Varunidae species, highlighting that symbiosis in the Thoracotremata evolved independently on multiple occasions. Different gene orders were detected in symbionts and free-living species when compared with the ancestral brachyuran gene order. Lastly, the selective pressure analysis detected two positively selected sites in the gene of Cryptochiridae, but the evidence for positive selection in Pinnotheridae and and was weak. Adaptive evolution of mitochondrial protein-coding genes is perhaps related to the presumably higher energetic demands of a symbiotic lifestyle.
Topics: Animals; Phylogeny; Brachyura; Symbiosis; Genes, Mitochondrial; Gene Order
PubMed: 37868050
DOI: 10.7717/peerj.16217 -
Genetics Apr 2024The maternal inheritance of mitochondria is a widely accepted paradigm, and mechanisms that prevent paternal mitochondria transmission to offspring during...
The maternal inheritance of mitochondria is a widely accepted paradigm, and mechanisms that prevent paternal mitochondria transmission to offspring during spermatogenesis and postfertilization have been described. Although certain species do retain paternal mitochondria, the factors affecting paternal mitochondria inheritance in these cases are unclear. More importantly, the evolutionary benefit of retaining paternal mitochondria and their ultimate fate are unknown. Here we show that transplanted exogenous paternal D. yakuba mitochondria can be transmitted to offspring when maternal mitochondria are dysfunctional in D. melanogaster. Furthermore, we show that the preserved paternal mitochondria are functional, and can be stably inherited, such that the proportion of paternal mitochondria increases gradually in subsequent generations. Our work has important implications that paternal mitochondria inheritance should not be overlooked as a genetic phenomenon in evolution, especially when paternal mitochondria are of significant differences from the maternal mitochondria or the maternal mitochondria are functionally abnormal. Our results improve the understanding of mitochondrial inheritance and provide a new model system for its study.
Topics: Male; Animals; DNA, Mitochondrial; Drosophila; Genes, Mitochondrial; Drosophila melanogaster; Mitochondria
PubMed: 38290047
DOI: 10.1093/genetics/iyae014 -
PloS One 2022Mitochondrial activity in cancer cells has been central to cancer research since Otto Warburg first published his thesis on the topic in 1956. Although Warburg proposed...
Mitochondrial activity in cancer cells has been central to cancer research since Otto Warburg first published his thesis on the topic in 1956. Although Warburg proposed that oxidative phosphorylation in the tricarboxylic acid (TCA) cycle was perturbed in cancer, later research has shown that oxidative phosphorylation is activated in most cancers, including prostate cancer (PCa). However, more detailed knowledge on mitochondrial metabolism and metabolic pathways in cancers is still lacking. In this study we expand our previously developed method for analyzing functional homologous proteins (FunHoP), which can provide a more detailed view of metabolic pathways. FunHoP uses results from differential expression analysis of RNA-Seq data to improve pathway analysis. By adding information on subcellular localization based on experimental data and computational predictions we can use FunHoP to differentiate between mitochondrial and non-mitochondrial processes in cancerous and normal prostate cell lines. Our results show that mitochondrial pathways are upregulated in PCa and that splitting metabolic pathways into mitochondrial and non-mitochondrial counterparts using FunHoP adds to the interpretation of the metabolic properties of PCa cells.
Topics: Male; Humans; Up-Regulation; Genes, Mitochondrial; Cell Line, Tumor; Oxidative Phosphorylation; Prostatic Neoplasms; Tricarboxylic Acids
PubMed: 36282866
DOI: 10.1371/journal.pone.0275621 -
Genetics in Medicine : Official Journal... Dec 2019A recent report has raised the possibility of biparental mitochondrial DNA (mtDNA) inheritance, which could lead to concerns by health-care professionals and patients...
PURPOSE
A recent report has raised the possibility of biparental mitochondrial DNA (mtDNA) inheritance, which could lead to concerns by health-care professionals and patients regarding investigations and genetic counseling of families with pathogenic mitochondrial DNA variants. Our aim was to examine the frequency of this phenomenon by investigating a cohort of patients with suspected mitochondrial disease.
METHODS
We studied genome sequencing (GS) data of DNA extracted from blood samples of 41 pediatric patients with suspected mitochondrial disease and their parents.
RESULTS
All of the mtDNA variants in the probands segregated with their mother or were apparently de novo. There were no variants that segregated only with the father and none of these families showed evidence of biparental inheritance of their mtDNA.
CONCLUSION
Paternal mitochondrial transmission is unlikely to be a common occurrence and therefore at this point we would not recommend changes in clinical practice.
Topics: Adult; Base Sequence; Child; Child, Preschool; DNA, Mitochondrial; Fathers; Female; Genes, Mitochondrial; Heredity; Humans; Male; Maternal Inheritance; Mitochondria; Mitochondrial Diseases; Mothers
PubMed: 31171843
DOI: 10.1038/s41436-019-0568-0