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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 -
Biochimica Et Biophysica Acta.... Feb 2021Different animal species have different characteristics regarding the transmission of mitochondrial DNA. While some species have biparental mitochondrial inheritance,... (Review)
Review
BACKGROUND
Different animal species have different characteristics regarding the transmission of mitochondrial DNA. While some species have biparental mitochondrial inheritance, others have developed pathways to remove paternal mtDNA. These pathways guarantee the uniparental mitochondrial inheritance, so far well known in mammals, avoiding heteroplasmy, which may have the potential to cause certain mitochondrial diseases in the offspring.
SCOPE OF REVIEW
This review aims to address the main mechanisms that involve mitochondrial degradation in different animal species, as well as to describe what is present in the literature on the mechanisms involved in mitochondrial inheritance.
MAJOR CONCLUSIONS
Two theories are proposed to explain the uniparental inheritance of mtDNA: (i) active degradation, where mechanisms for paternal mitochondrial DNA elimination involve mitochondrial degradation pathway by autophagy and, in some species, may also involve the endocytic degradation pathway; and (ii) passive dilution, where the paternal mitochondria are diluted in the cells of the embryo according to cell division, until becoming undetectable.
GENERAL SIGNIFICANCE
This work brings a wide review of the already published evidence on mitochondrial inheritance in the animal kingdom and the possible mechanisms to mtDNA transmission already described in literature.
Topics: Animals; DNA, Mitochondrial; Embryo, Mammalian; Endocytosis; Fertilization; Male; Mitochondria; Mitophagy; Spermatozoa; Ubiquitination
PubMed: 33276010
DOI: 10.1016/j.bbamcr.2020.118916 -
Philosophical Transactions of the Royal... May 2021The first animal mitochondrial genomes to be sequenced were of several vertebrates and model organisms, and the consistency of genomic features found has led to a... (Review)
Review
The first animal mitochondrial genomes to be sequenced were of several vertebrates and model organisms, and the consistency of genomic features found has led to a 'textbook description'. However, a more broad phylogenetic sampling of complete animal mitochondrial genomes has found many cases where these features do not exist, and the phylum Mollusca is especially replete with these exceptions. The characterization of full mollusc mitogenomes required considerable effort involving challenging molecular biology, but has created an enormous catalogue of surprising deviations from that textbook description, including wide variation in size, radical genome rearrangements, gene duplications and losses, the introduction of novel genes, and a complex system of inheritance dubbed 'doubly uniparental inheritance'. Here, we review the extraordinary variation in architecture, molecular functioning and intergenerational transmission of molluscan mitochondrial genomes. Such features represent a great potential for the discovery of biological history, processes and functions that are novel for animal mitochondrial genomes. This provides a model system for studying the evolution and the manifold roles that mitochondria play in organismal physiology, and many ways that the study of mitochondrial genomes are useful for phylogeny and population biology. This article is part of the Theo Murphy meeting issue 'Molluscan genomics: broad insights and future directions for a neglected phylum'.
Topics: Animals; Gene Duplication; Gene Rearrangement; Genome, Mitochondrial; Heredity; Mollusca
PubMed: 33813887
DOI: 10.1098/rstb.2020.0159 -
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 -
PLoS Pathogens Feb 2022Genetic exchange among disease-causing micro-organisms can generate progeny that combine different pathogenic traits. Though sexual reproduction has been described in...
Genetic exchange among disease-causing micro-organisms can generate progeny that combine different pathogenic traits. Though sexual reproduction has been described in trypanosomes, its impact on the epidemiology of Human African Trypanosomiasis (HAT) remains controversial. However, human infective and non-human infective strains of Trypanosoma brucei circulate in the same transmission cycles in HAT endemic areas in subsaharan Africa, providing the opportunity for mating during the developmental cycle in the tsetse fly vector. Here we investigated inheritance among progeny from a laboratory cross of T. brucei and then applied these insights to genomic analysis of field-collected isolates to identify signatures of past genetic exchange. Genomes of two parental and four hybrid progeny clones with a range of DNA contents were assembled and analysed by k-mer and single nucleotide polymorphism (SNP) frequencies to determine heterozygosity and chromosomal inheritance. Variant surface glycoprotein (VSG) genes and kinetoplast (mitochondrial) DNA maxi- and minicircles were extracted from each genome to examine how each of these components was inherited in the hybrid progeny. The same bioinformatic approaches were applied to an additional 37 genomes representing the diversity of T. brucei in subsaharan Africa and T. evansi. SNP analysis provided evidence of crossover events affecting all 11 pairs of megabase chromosomes and demonstrated that polyploid hybrids were formed post-meiotically and not by fusion of the parental diploid cells. VSGs and kinetoplast DNA minicircles were inherited biparentally, with approximately equal numbers from each parent, whereas maxicircles were inherited uniparentally. Extrapolation of these findings to field isolates allowed us to distinguish clonal descent from hybridization by comparing maxicircle genotype to VSG and minicircle repertoires. Discordance between maxicircle genotype and VSG and minicircle repertoires indicated inter-lineage hybridization. Significantly, some of the hybridization events we identified involved human infective and non-human infective trypanosomes circulating in the same geographic areas.
Topics: Animals; DNA, Kinetoplast; DNA, Mitochondrial; DNA, Protozoan; Genotype; Humans; Hybridization, Genetic; Trypanosoma; Trypanosoma brucei brucei; Trypanosomiasis, African
PubMed: 35139131
DOI: 10.1371/journal.ppat.1010300 -
Frontiers in Molecular Neuroscience 2023Parkinson's disease (PD) is the second most common neurodegenerative disease with currently no cure. Most PD cases are sporadic, and about 5-10% of PD cases present a... (Review)
Review
Parkinson's disease (PD) is the second most common neurodegenerative disease with currently no cure. Most PD cases are sporadic, and about 5-10% of PD cases present a monogenic inheritance pattern. Mutations in more than 20 genes are associated with genetic forms of PD. Mitochondrial dysfunction is considered a prominent player in PD pathogenesis. Post-translational modifications (PTMs) allow rapid switching of protein functions and therefore impact various cellular functions including those related to mitochondria. Among the PD-associated genes, , , and encode enzymes that directly involved in catalyzing PTM modifications of target proteins, while others like α-synuclein, FBXO7, HTRA2, VPS35, CHCHD2, and DJ-1, undergo substantial PTM modification, subsequently altering mitochondrial functions. Here, we summarize recent findings on major PTMs associated with PD-related proteins, as enzymes or substrates, that are shown to regulate important mitochondrial functions and discuss their involvement in PD pathogenesis. We will further highlight the significance of PTM-regulated mitochondrial functions in understanding PD etiology. Furthermore, we emphasize the potential for developing important biomarkers for PD through extensive research into PTMs.
PubMed: 38273938
DOI: 10.3389/fnmol.2023.1329554 -
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 -
The EMBO Journal Sep 2023Replication of the mitochondrial genome and expression of the genes it encodes both depend on a sufficient supply of nucleotides to mitochondria. Accordingly,...
Replication of the mitochondrial genome and expression of the genes it encodes both depend on a sufficient supply of nucleotides to mitochondria. Accordingly, dysregulated nucleotide metabolism not only destabilises the mitochondrial genome, but also affects its transcription. Here, we report that a mitochondrial nucleoside diphosphate kinase, NME6, supplies mitochondria with pyrimidine ribonucleotides that are necessary for the transcription of mitochondrial genes. Loss of NME6 function leads to the depletion of mitochondrial transcripts, as well as destabilisation of the electron transport chain and impaired oxidative phosphorylation. These deficiencies are rescued by an exogenous supply of pyrimidine ribonucleosides. Moreover, NME6 is required for the maintenance of mitochondrial DNA when the access to cytosolic pyrimidine deoxyribonucleotides is limited. Our results therefore reveal an important role for ribonucleotide salvage in mitochondrial gene expression.
Topics: Genes, Mitochondrial; Pyrimidines; Mitochondria; Nucleotides; DNA, Mitochondrial; Ribonucleotides
PubMed: 37439264
DOI: 10.15252/embj.2022113256 -
International Journal of Molecular... May 2020Mitochondria are important organelles in eukaryotes that provide energy for cellular processes. Their function is highly conserved and depends on the expression of... (Review)
Review
Mitochondria are important organelles in eukaryotes that provide energy for cellular processes. Their function is highly conserved and depends on the expression of nuclear encoded genes and genes encoded in the organellar genome. Mitochondrial DNA replication is independent of the replication control of nuclear DNA and as such, mitochondria may behave as selfish elements, so they need to be controlled, maintained and reliably inherited to progeny. Phytopathogenic fungi meet with special environmental challenges within the plant host that might depend on and influence mitochondrial functions and services. We find that this topic is basically unexplored in the literature, so this review largely depends on work published in other systems. In trying to answer elemental questions on mitochondrial functioning, we aim to introduce the aspect of mitochondrial functions and services to the study of plant-microbe-interactions and stimulate phytopathologists to consider research on this important organelle in their future projects.
Topics: Basidiomycota; Cell Nucleus; Cryptococcus neoformans; DNA, Mitochondrial; Fungi; Genes, Fungal; Haploidy; Saccharomyces
PubMed: 32485941
DOI: 10.3390/ijms21113883 -
International Journal of Molecular... Jan 2022Cardiovascular diseases (CVD) are one of the leading causes of morbidity and mortality worldwide. mtDNA (mitochondrial DNA) mutations are known to participate in the... (Review)
Review
Cardiovascular diseases (CVD) are one of the leading causes of morbidity and mortality worldwide. mtDNA (mitochondrial DNA) mutations are known to participate in the development and progression of some CVD. Moreover, specific types of mitochondria-mediated CVD have been discovered, such as MIEH (maternally inherited essential hypertension) and maternally inherited CHD (coronary heart disease). Maternally inherited mitochondrial CVD is caused by certain mutations in the mtDNA, which encode structural mitochondrial proteins and mitochondrial tRNA. In this review, we focus on recently identified mtDNA mutations associated with CVD (coronary artery disease and hypertension). Additionally, new data suggest the role of mtDNA mutations in Brugada syndrome and ischemic stroke, which before were considered only as a result of mutations in nuclear genes. Moreover, we discuss the molecular mechanisms of mtDNA involvement in the development of the disease.
Topics: Cardiovascular Diseases; DNA, Mitochondrial; Genetic Predisposition to Disease; Humans; Maternal Inheritance; Mitochondria; Mutation
PubMed: 35055137
DOI: 10.3390/ijms23020952