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Nature Apr 2013Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis. Here we show...
Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis. Here we show that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1β but not tumour-necrosis factor-α in mouse macrophages. A comprehensive metabolic map of lipopolysaccharide-activated macrophages shows upregulation of glycolytic and downregulation of mitochondrial genes, which correlates directly with the expression profiles of altered metabolites. Lipopolysaccharide strongly increases the levels of the tricarboxylic-acid cycle intermediate succinate. Glutamine-dependent anerplerosis is the principal source of succinate, although the 'GABA (γ-aminobutyric acid) shunt' pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1α, an effect that is inhibited by 2-deoxyglucose, with interleukin-1β as an important target. Lipopolysaccharide also increases succinylation of several proteins. We therefore identify succinate as a metabolite in innate immune signalling, which enhances interleukin-1β production during inflammation.
Topics: Animals; Bone Marrow Cells; Citric Acid Cycle; Deoxyglucose; Down-Regulation; Genes, Mitochondrial; Glutamine; Glycolysis; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Immunity, Innate; Inflammation; Interleukin-1beta; Lipopolysaccharides; Macrophages; Mice; Signal Transduction; Succinic Acid; Up-Regulation; gamma-Aminobutyric Acid
PubMed: 23535595
DOI: 10.1038/nature11986 -
Proceedings of the National Academy of... Dec 2018Although there has been considerable debate about whether paternal mitochondrial DNA (mtDNA) transmission may coexist with maternal transmission of mtDNA, it is...
Although there has been considerable debate about whether paternal mitochondrial DNA (mtDNA) transmission may coexist with maternal transmission of mtDNA, it is generally believed that mitochondria and mtDNA are exclusively maternally inherited in humans. Here, we identified three unrelated multigeneration families with a high level of mtDNA heteroplasmy (ranging from 24 to 76%) in a total of 17 individuals. Heteroplasmy of mtDNA was independently examined by high-depth whole mtDNA sequencing analysis in our research laboratory and in two Clinical Laboratory Improvement Amendments and College of American Pathologists-accredited laboratories using multiple approaches. A comprehensive exploration of mtDNA segregation in these families shows biparental mtDNA transmission with an autosomal dominantlike inheritance mode. Our results suggest that, although the central dogma of maternal inheritance of mtDNA remains valid, there are some exceptional cases where paternal mtDNA could be passed to the offspring. Elucidating the molecular mechanism for this unusual mode of inheritance will provide new insights into how mtDNA is passed on from parent to offspring and may even lead to the development of new avenues for the therapeutic treatment for pathogenic mtDNA transmission.
Topics: Adult; Child, Preschool; DNA, Mitochondrial; Databases, Genetic; Female; Genes, Mitochondrial; Genome, Mitochondrial; Humans; Inheritance Patterns; Male; Maternal Inheritance; Middle Aged; Mitochondria; Mitochondrial Diseases; Paternal Inheritance; Pedigree
PubMed: 30478036
DOI: 10.1073/pnas.1810946115 -
Current Protocols in Mouse Biology Mar 2017Mitochondrial DNA (mtDNA) lacks the protection provided by the nucleosomes in the nuclear DNA and does not have a DNA repair mechanism, making it highly susceptible to...
Mitochondrial DNA (mtDNA) lacks the protection provided by the nucleosomes in the nuclear DNA and does not have a DNA repair mechanism, making it highly susceptible to damage, which can lead to mtDNA depletion. mtDNA depletion compromises the efficient function of cells and tissues and thus impacts negatively on health. Here, we describe a brief and easy protocol to quantify mtDNA copy number by determining the mtDNA/nDNA ratio. The procedure has been validated using a cohort of young and aged mice. © 2017 by John Wiley & Sons, Inc.
Topics: Age Factors; Animals; Cell Nucleus; DNA; DNA, Mitochondrial; Gene Dosage; Genes, Mitochondrial; Mice; Polymerase Chain Reaction; Reproducibility of Results
PubMed: 28252199
DOI: 10.1002/cpmo.21 -
ELife Jul 2023The degradation of sperm-borne mitochondria after fertilization is a conserved event. This process known as post-fertilization sperm mitophagy, ensures exclusively...
The degradation of sperm-borne mitochondria after fertilization is a conserved event. This process known as post-fertilization sperm mitophagy, ensures exclusively maternal inheritance of the mitochondria-harbored mitochondrial DNA genome. This mitochondrial degradation is in part carried out by the ubiquitin-proteasome system. In mammals, ubiquitin-binding pro-autophagic receptors such as SQSTM1 and GABARAP have also been shown to contribute to sperm mitophagy. These systems work in concert to ensure the timely degradation of the sperm-borne mitochondria after fertilization. We hypothesize that other receptors, cofactors, and substrates are involved in post-fertilization mitophagy. Mass spectrometry was used in conjunction with a porcine cell-free system to identify other autophagic cofactors involved in post-fertilization sperm mitophagy. This porcine cell-free system is able to recapitulate early fertilization proteomic interactions. Altogether, 185 proteins were identified as statistically different between control and cell-free-treated spermatozoa. Six of these proteins were further investigated, including MVP, PSMG2, PSMA3, FUNDC2, SAMM50, and BAG5. These proteins were phenotyped using porcine in vitro fertilization, cell imaging, proteomics, and the porcine cell-free system. The present data confirms the involvement of known mitophagy determinants in the regulation of mitochondrial inheritance and provides a master list of candidate mitophagy co-factors to validate in the future hypothesis-driven studies.
Topics: Male; Swine; Animals; Fertilization; Genes, Mitochondrial; Cell-Free System; Proteomics; Semen; Spermatozoa; DNA, Mitochondrial; Mammals; Ubiquitin
PubMed: 37470242
DOI: 10.7554/eLife.85596 -
Current Opinion in Genetics &... Jun 2023In contrast with nuclear genes that are passed on through both parents, mitochondrial genes are maternally inherited in most species, most of the time. The genetic... (Review)
Review
In contrast with nuclear genes that are passed on through both parents, mitochondrial genes are maternally inherited in most species, most of the time. The genetic conflict stemming from this transmission asymmetry is well-documented, and there is an abundance of population-genetic theory associated with it. While occasional or aberrant paternal inheritance occurs, there are only a few cases where exclusive paternal inheritance of mitochondrial genomes is the evolved state. Why this is remains poorly understood. By examining commonalities between species with exclusive paternal inheritance, we discuss what they may tell us about the evolutionary forces influencing mitochondrial inheritance patterns. We end by discussing recent technological advances that make exploring the causes and consequences of paternal inheritance feasible.
Topics: Paternal Inheritance; Mitochondria; Inheritance Patterns; Genes, Mitochondrial; Genome, Mitochondrial; DNA, Mitochondrial
PubMed: 37245242
DOI: 10.1016/j.gde.2023.102053 -
Molecular Biology and Evolution Aug 2015Eukaryotes were born of a chimeric union between two prokaryotes--the progenitors of the mitochondrial and nuclear genomes. Early in eukaryote evolution, most... (Review)
Review
Eukaryotes were born of a chimeric union between two prokaryotes--the progenitors of the mitochondrial and nuclear genomes. Early in eukaryote evolution, most mitochondrial genes were lost or transferred to the nucleus, but a core set of genes that code exclusively for products associated with the electron transport system remained in the mitochondrion. The products of these mitochondrial genes work in intimate association with the products of nuclear genes to enable oxidative phosphorylation and core energy production. The need for coadaptation, the challenge of cotransmission, and the possibility of genomic conflict between mitochondrial and nuclear genes have profound consequences for the ecology and evolution of eukaryotic life. An emerging interdisciplinary field that I call "mitonuclear ecology" is reassessing core concepts in evolutionary ecology including sexual reproduction, two sexes, sexual selection, adaptation, and speciation in light of the interactions of mitochondrial and nuclear genomes.
Topics: Animals; Cell Nucleus; Evolution, Molecular; Genes, Mitochondrial; Genome, Mitochondrial; Humans; Mitochondria
PubMed: 25931514
DOI: 10.1093/molbev/msv104 -
Science Advances Aug 2023Genes for cardiolipin and ceramide synthesis occur in some alphaproteobacterial genomes. They shed light on mitochondrial origin and signaling in the first eukaryotic... (Review)
Review
Genes for cardiolipin and ceramide synthesis occur in some alphaproteobacterial genomes. They shed light on mitochondrial origin and signaling in the first eukaryotic cells.
Topics: Symbiosis; Mitochondria; Eukaryotic Cells; Genes, Mitochondrial; Phylogeny; Biological Evolution; Evolution, Molecular
PubMed: 37556561
DOI: 10.1126/sciadv.adj4493 -
Physiological Genomics Jul 2023Mitochondrial dysfunction has been implicated in pregnancy-induced hypertension (PIH). The role of mitochondrial gene dysregulation in PIH, and consequences for...
Mitochondrial dysfunction has been implicated in pregnancy-induced hypertension (PIH). The role of mitochondrial gene dysregulation in PIH, and consequences for maternal-fetal interactions, remain elusive. Here, we investigated mitochondrial gene expression and dysregulation in maternal and placental tissues from pregnancies with and without PIH; further, we measured circulating mitochondrial DNA (mtDNA) mutational load, an index of mtDNA integrity. Differential gene expression analysis followed by Time Course Gene Set Analysis (TcGSA) was conducted on publicly available high throughput sequencing transcriptomic data sets. Mutational load analysis was carried out on peripheral mononuclear blood cells from healthy pregnant individuals and individuals with preeclampsia. Thirty mitochondrial differentially expressed genes (mtDEGs) were detected in the maternal cell-free circulating transcriptome, whereas nine were detected in placental transcriptome from pregnancies with PIH. In PIH pregnancies, maternal mitochondrial dysregulation was associated with pathways involved in inflammation, cell death/survival, and placental development, whereas fetal mitochondrial dysregulation was associated with increased production of extracellular vesicles (EVs) at term. Mothers with preeclampsia did not exhibit a significantly different degree of mtDNA mutational load. Our findings support the involvement of maternal mitochondrial dysregulation in the pathophysiology of PIH and suggest that mitochondria may mediate maternal-fetal interactions during healthy pregnancy. This study identifies aberrant maternal and fetal expression of mitochondrial genes in pregnancies with gestational hypertension and preeclampsia. Mitochondrial gene dysregulation may be a common etiological factor contributing to the development of de novo hypertension in pregnancy-associated hypertensive disorders.
Topics: Pregnancy; Female; Humans; Hypertension, Pregnancy-Induced; Placenta; Pre-Eclampsia; Genes, Mitochondrial; DNA, Mitochondrial
PubMed: 37184228
DOI: 10.1152/physiolgenomics.00005.2023 -
Genome Oct 2015Mitochondrial DNA (mtDNA) is predominantly maternally inherited in eukaryotes. Diverse molecular mechanisms underlying the phenomenon of strict maternal inheritance... (Review)
Review
Mitochondrial DNA (mtDNA) is predominantly maternally inherited in eukaryotes. Diverse molecular mechanisms underlying the phenomenon of strict maternal inheritance (SMI) of mtDNA have been described, but the evolutionary forces responsible for its predominance in eukaryotes remain to be elucidated. Exceptions to SMI have been reported in diverse eukaryotic taxa, leading to the prediction that several distinct molecular mechanisms controlling mtDNA transmission are present among the eukaryotes. We propose that these mechanisms will be better understood by studying the deviations from the predominating pattern of SMI. This minireview summarizes studies on eukaryote species with unusual or rare mitochondrial inheritance patterns, i.e., other than the predominant SMI pattern, such as maternal inheritance of stable heteroplasmy, paternal leakage of mtDNA, biparental and strictly paternal inheritance, and doubly uniparental inheritance of mtDNA. The potential genes and mechanisms involved in controlling mitochondrial inheritance in these organisms are discussed. The linkage between mitochondrial inheritance and sex determination is also discussed, given that the atypical systems of mtDNA inheritance examined in this minireview are frequently found in organisms with uncommon sexual systems such as gynodioecy, monoecy, or andromonoecy. The potential of deviations from SMI for facilitating a better understanding of a number of fundamental questions in biology, such as the evolution of mtDNA inheritance, the coevolution of nuclear and mitochondrial genomes, and, perhaps, the role of mitochondria in sex determination, is considerable.
Topics: Animals; DNA, Mitochondrial; Eukaryota; Evolution, Molecular; Female; Genes, Dominant; Genes, Mitochondrial; Genetic Variation; Genome, Mitochondrial; Humans; Inheritance Patterns; Male; Mitochondria; Sex Determination Processes
PubMed: 26501689
DOI: 10.1139/gen-2015-0090 -
Current Neuropharmacology 2022Mitochondrial disorders are clinically heterogeneous, resulting from nuclear gene and mitochondrial mutations that disturb the mitochondrial functions and dynamics.... (Review)
Review
Mitochondrial disorders are clinically heterogeneous, resulting from nuclear gene and mitochondrial mutations that disturb the mitochondrial functions and dynamics. There is a lack of evidence linking mtDNA mutations to neurodegenerative disorders, mainly due to the absence of noticeable neuropathological lesions in postmortem samples. This review describes various gene mutations in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and stroke. These abnormalities, including PINK1, Parkin, and SOD1 mutations, seem to reveal mitochondrial dysfunctions due to either mtDNA mutation or deletion, the mechanism of which remains unclear in depth.
Topics: Amyotrophic Lateral Sclerosis; DNA, Mitochondrial; Genes, Mitochondrial; Humans; Mitochondrial Diseases; Mutation; Neurodegenerative Diseases; Parkinson Disease
PubMed: 34503413
DOI: 10.2174/1570159X19666210908163839