Mitochondrial Inheritance Patterns Research Articles

Investigating the role of mitochondrial membrane potential in paternal inheritance of mitochondria

Abstract The process of oxidative phosphorylation (OXPHOS) in mitochondria depends on an electrochemical gradient known as the mitochondrial membrane potential (Δψm). Reflecting high functionality, elevated Δψm usually depicts healthy mitochondria and contributes to organelle selection. This study investigates whether mitochondrial properties linked with bioenergetics, such as Δψm, play a role in paternal inheritance of mitochondria. More specifically, the study looks at how sperm Δψm responds to egg chemoattractants in bivalves characterized by distinct mitochondrial inheritance patterns: strict maternal inheritance (SMI) and doubly uniparental inheritance (DUI), the latter displaying sex-specific transmission of paternal mitochondrial DNA. Sperm Δψm was examined in four bivalve species: the blue mussel (Mytilus edulis) and the Manila clam (Ruditapes philippinarum) (DUI), plus the hard clam (Mercenaria mercenaria) and the soft-shell clam (Mya arenaria) (SMI). In the absence of egg chemoattractants, sperm Δψm did not vary between the two groups. However, there was a trend of increase in Δψm following egg detection only in sperm bearing paternally derived mitochondria (DUI). This suggests, along with bioenergetic changes, that Δψm modulation might be a specific property of at least some DUI species, possibly implicated in their unique ability to transmit their mitochondria in a sex-specific fashion.

Next-generation sequencing improves precision medicine in hearing loss.

Background: An early etiological diagnosis of hearing loss positively impacts children's quality of life including language and cognitive development. Even though hearing loss associates with extremely high genetic and allelic heterogeneity, several studies have proven that Next-Generation Sequencing (NGS)-based gene panel testing significantly reduces the time between onset and diagnosis. Methods: In order to assess the clinical utility of our custom NGS GHELP panel, the prevalence of pathogenic single nucleotide variants, indels or copy number variants was assessed by sequencing 171 nuclear and 8 mitochondrial genes in 155 Spanish individuals with hearing loss. Results: A genetic diagnosis of hearing loss was achieved in 34% (52/155) of the individuals (5 out of 52 were syndromic). Among the diagnosed cases, 87% (45/52) and 12% (6/52) associated with autosomal recessive and dominant inheritance patterns respectively; remarkably, 2% (1/52) associated with mitochondrial inheritance pattern. Although the most frequently mutated genes in this cohort were consistent with those described in the literature (GJB2, OTOF or MYO7A), causative variants in less frequent genes such as TMC1, FGF3 or mitCOX1 were also identified. Moreover, 5% of the diagnosed cases (3/52) were associated with pathogenic copy number variants. Conclusion: The clinical utility of NGS panels that allows identification of different types of pathogenic variants-not only single nucleotide variants/indels in both nuclear and mitochondrial genes but also copy number variants-has been demonstrated to reduce the clinical diagnostic odyssey in hearing loss. Thus, clinical implementation of genomic strategies within the regular clinical practice, and, more significantly, within the newborn screening protocols, is warranted.

Unparalleled mitochondrial heteroplasmy and Wolbachia co-infection in the non-model bee, Amphylaeus morosus.

Mitochondrial heteroplasmy is the occurrence of more than one type of mitochondrial DNA within a single individual. Although generally reported to occur in a small subset of individuals within a species, there are some instances of widespread heteroplasmy across entire populations. Amphylaeus morosus is an Australian native bee species in the diverse and cosmopolitan bee family Colletidae. This species has an extensive geographical range along the eastern Australian coast, from southern Queensland to western Victoria, covering approximately 2,000 km. Seventy individuals were collected from five localities across this geographical range and sequenced using Sanger sequencing for the mitochondrial cytochrome c oxidase subunit I (COI) gene. These data indicate that every individual had the same consistent heteroplasmic sites but no other nucleotide variation, suggesting two conserved and widespread heteroplasmic mitogenomes. Ion Torrent shotgun sequencing revealed that heteroplasmy occurred across multiple mitochondrial protein-coding genes and is unlikely explained by transposition of mitochondrial genes into the nuclear genome (NUMTs). DNA sequence data also demonstrated a consistent co-infection of Wolbachia across the A. morosus distribution with every individual infected with both bacterial strains. Our data are consistent with the presence of two mitogenomes within all individuals examined in this species and suggest a major divergence from standard patterns of mitochondrial inheritance. Because the host's mitogenome and the Wolbachia genome are genetically linked through maternal inheritance, we propose three possible hypotheses that could explain maintenance of the widespread and conserved co-occurring bacterial and mitochondrial genomes in this species.

Maternal transmission of mitochondrial diseases.

Given the major role of the mitochondrion in cellular homeostasis, dysfunctions of this organelle may lead to several common diseases in humans. Among these, maternal diseases linked to mitochondrial DNA (mtDNA) mutations are of special interest due to the unclear pattern of mitochondrial inheritance. Multiple copies of mtDNA are present in a cell, each encoding for 37 genes essential for mitochondrial function. In cases of mtDNA mutations, mitochondrial malfunctioning relies on mutation load, as mutant and wild-type molecules may co-exist within the cell. Since the mutation load associated with disease manifestation varies for different mutations and tissues, it is hard to predict the progeny phenotype based on mutation load in the progenitor. In addition, poorly understood mechanisms act in the female germline to prevent the accumulation of deleterious mtDNA in the following generations. In this review, we outline basic aspects of mitochondrial inheritance in mammals and how they may lead to maternally-inherited diseases. Furthermore, we discuss potential therapeutic strategies for these diseases, which may be used in the future to prevent their transmission.

Unusual Patterns of Mitochondrial Inheritance in the Brown Alga Ectocarpus.

Most eukaryotes inherit their mitochondria from only one of their parents. When there are different sexes, it is almost always the maternal mitochondria that are transmitted. Indeed, maternal uniparental inheritance has been reported for the brown alga Ectocarpus but we show in this study that different strains of Ectocarpus can exhibit different patterns of inheritance: Ectocarpus siliculosus strains showed maternal uniparental inheritance, as expected, but crosses using different Ectocarpus species 7 strains exhibited either paternal uniparental inheritance or an unusual pattern of transmission where progeny inherited either maternal or paternal mitochondria, but not both. A possible correlation between the pattern of mitochondrial inheritance and male gamete parthenogenesis was investigated. Moreover, in contrast to observations in the green lineage, we did not detect any change in the pattern of mitochondrial inheritance in mutant strains affected in life cycle progression. Finally, an analysis of field-isolated strains provided evidence of mitochondrial genome recombination in both Ectocarpus species.

Whole exome sequencing identifies both nuclear and mitochondrial variations in an Iranian family with non-syndromic hearing loss

Genetic contributing factors to non-syndromic hearing loss (NSHL) are remarkably diverse spanning over autosomal to X-linked to mitochondrial inheritance patterns. Facing a quite unconventional pedigree, here we report implementation of whole exome sequencing (WES) to uncover mitochondrial pathogenic variant in a six-generation Iranian family with four cases affected with hereditary NSHL of variable severity. As a result, heteroplasmic transition of A to G at position 1555 of MT-RNR1 gene was identified in all affected individuals co-existing with nuclear c.28G > T (p.A10S) variant in the TRMU gene, only in some patients. The reliability of WES to infer nuclear as well as mitochondrial variants in hearing loss were discussed.

Lose it or keep it: (how bivalves can provide) insights into mitochondrial inheritance mechanisms.

The strictly maternal inheritance (SMI) is a pattern of mitochondrial inheritance observed across the whole animal kingdom. However, some interesting exceptions are known for the class Bivalvia, in which several species show an unusual pattern called doubly uniparental inheritance (DUI) whose outcome is a heteroplasmic pool of mtDNA in males. Even if DUI has been studied for long, its molecular basis has not been established yet. The aim of this work is to select classes of proteins known to be involved in the maintenance of SMI and to compare their features in two clam species differing for their mitochondrial inheritance mechanism, that is, the SMI species Ruditapes decussatus and the DUI species Ruditapes philippinarum. Data have been obtained from the transcriptomes of male and female ripe gonads of both species. Our analysis focused on nucleases and polymerases, ubiquitination and ubiquitin-like modifier pathways, and proteins involved in autophagy and mitophagy. For each protein group of interest, transcription bias (male or female), annotation, and mitochondrial targeting (when appropriate) were assessed. We did not find evidence supporting a role of nucleases/polymerases or autophagic machinery in the enforcement of SMI in R. decussatus. On the other hand, ubiquitinating enzymes with the expected features have been retrieved, providing us with two alternative testable models for mitochondrial inheritance mechanisms at the molecular level.

Fluorescent sperm offer a method for tracking the real-time success of ejaculates when they compete to fertilise eggs.

Despite intensive research effort, many uncertainties remain in the field of gamete-level sexual selection, particularly in understanding how sperm from different males interact when competing for fertilisations. Here, we demonstrate the utility of broadcast spawning marine invertebrates for unravelling these mysteries, highlighting their mode of reproduction and, in some species, unusual patterns of mitochondrial inheritance. We present a method utilising both properties in the blue mussel, Mytilus galloprovincialis. In mytilids and many other bivalves, both sperm and egg mitochondria are inherited. We exploit this, using the vital mitochondrial dye MitoTracker, to track the success of sperm from individual males when they compete with those from rivals to fertilise eggs. We confirm that dying mitochondria has no adverse effects on in vitro measures of sperm motility (reflecting mitochondrial energetics) or sperm competitive fertilisation success. Therefore, we propose the technique as a powerful and logistically tractable tool for sperm competition studies. Importantly, our method allows the competitive fertilisation success of sperm from any male to be measured directly and disentangled from confounding effects of post-fertilisation embryo survival. Moreover, the mitochondrial dye has broader applications in taxa without paternal mitochondrial inheritance, for example by tracking the dynamics of competing ejaculates prior to fertilisation.

Wolbachiaendosymbionts distort DNA barcoding in the parasitoid wasp genusDiplazon(Hymenoptera: Ichneumonidae)

Molecular species delimitation has the potential to speed up both discovery and description rates for new species. However, several studies have shown a limited performance of the standard DNA barcoding approach which relies on a single mitochondrial gene, cytochrome oxidase 1 (COI). Besides incomplete lineage sorting or a low substitution rate, distortion of mitochondrial inheritance patterns by bacterial endosymbionts could explain the failure of barcoding. Numerous reviews have discussed this phenomenon, but only few empirical examples exist. In the present study, we examine the effect of Wolbachia bacteria on barcoding in the parasitoid wasp genus Diplazon. Although integrative taxonomy recognizes 16 species, COI only recovers up to ten. Adding multivariate morphometrics, genotyping a fast-evolving nuclear gene (ITS2) and screening the Diplazon species for Wolbachia, we show that the failure of DNA barcoding coincides with the presence of the endosymbiont. Two species even share identical COI haplotypes and Wolbachia strains, even though ITS2 suggests that they are not closely related. This is one of very few examples of mitochondrial DNA introgression between well-established insect species, facilitated by Wolbachia. We review similar reports, provide a list of criteria to identify endosymbiont-mediated introgression, and discuss the prevalence and impact of this phenomenon on insect systematics and evolution.

Atypical mitochondrial inheritance patterns in eukaryotes.

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.

Mitochondrial DNA inheritance in the human fungal pathogen Cryptococcus gattii

The inheritance of mitochondrial DNA (mtDNA) is predominantly uniparental in most sexual eukaryotes. In this study, we examined the mitochondrial inheritance pattern of Cryptococcus gattii, a basidiomycetous yeast responsible for the recent and ongoing outbreak of cryptococcal infections in the US Pacific Northwest and British Columbia (especially Vancouver Island) in Canada. Using molecular markers, we analyzed the inheritance of mtDNA in 14 crosses between strains within and between divergent lineages in C. gattii. Consistent with results from recent studies, our analyses identified significant variations in mtDNA inheritance patterns among strains and crosses, ranging from strictly uniparental to biparental. For two of the crosses that showed uniparental mitochondrial inheritance in standard laboratory conditions, we further investigated the effects of the following environmental variables on mtDNA inheritance: UV exposure, temperature, and treatments with the methylation inhibitor 5-aza-2′-deoxycytidine and with the ubiquitination inhibitor ammonium chloride. Interestingly, one of these crosses showed no response to these environmental variables while the other exhibited diverse patterns ranging from complete uniparental inheritance of the MATa parent mtDNA, to biparental inheritance, and to a significant bias toward inheritance of the MATα parental mtDNA. Our results indicate that mtDNA inheritance in C. gattii differs from that in its closely related species Cryptococcus neoformans.

Left ventricular noncompaction cardiomyopathy: updated review

The first case of noncompaction was described in 1932 after an autopsy performed on a newborn infant with aortic atresia/coronary-ventricular fistula. Isolated noncompaction cardiomyopathy was first described in 1984. A review on selected/relevant medical literature was conducted using Pubmed from 1984 to 2013 and the pathogenesis, clinical features, and management are discussed. Left ventricular noncompaction (LVNC) is a relatively rare congenital condition that results from arrest of the normal compaction process of the myocardium during fetal development. LVNC shows variability in its genetic pattern, pathophysiologic findings, and clinical presentations. The genetic heterogeneity, phenotypical overlap, and variety in clinical presentation raised the suspicion that LVNC might just be a morphological variant of other cardiomyopathies, but the American Heart Association classifies LVNC as a primary genetic cardiomyopathy. The familiar type is common and follows a X-linked, autosomal-dominant, or mitochondrial-inheritance pattern (in children). LVNC can occur in isolation or coexist with other cardiac and/or systemic anomalies. The clinical presentations are variable ranging from asymptomatic patients to patients who develop ventricular arrhythmias, thromboembolism, heart failure, and sudden cardiac death. Increased awareness over the last 25 years and improvements in technology have increased the identification of this illness and improved the clinical outcome and prognosis. LVNC is commonly diagnosed by echocardiography. Other useful diagnostic techniques for LVNC include cardiac magnetic resonance imaging, computerized tomography, and left ventriculography. Management is symptom based and patients with symptoms have a poorer prognosis. LVNC is a genetically heterogeneous disorder which can be associated with other anomalies. Making the correct diagnosis is important because of the possible associations and the need for long-term management and screening of living relatives.

Maternal inheritance of mitochondrial genomes and complex inheritance of chloroplast genomes in Actinidia Lind.: evidences from interspecific crosses

The inheritance pattern of chloroplast and mitochondria is a critical determinant in studying plant phylogenetics, biogeography and hybridization. To better understand chloroplast and mitochondrial inheritance patterns in Actinidia (traditionally called kiwifruit), we performed 11 artificial interspecific crosses and studied the ploidy levels, morphology, and sequence polymorphisms of chloroplast DNA (cpDNA) and mitochondrial DNA (mtDNA) of parents and progenies. Sequence analysis showed that the mtDNA haplotypes of F1 hybrids entirely matched those of the female parents, indicating strictly maternal inheritance of Actinidia mtDNA. However, the cpDNA haplotypes of F1 hybrids, which were predominantly derived from the male parent (9 crosses), could also originate from the mother (1 cross) or both parents (1 cross), demonstrating paternal, maternal, and biparental inheritance of Actinidia cpDNA. The inheritance patterns of the cpDNA in Actinidia hybrids differed according to the species and genotypes chosen to be the parents, rather than the ploidy levels of the parent selected. The multiple inheritance modes of Actinidia cpDNA contradicted the strictly paternal inheritance patterns observed in previous studies, and provided new insights into the use of cpDNA markers in studies of phylogenetics, biogeography and introgression in Actinidia and other angiosperms.

Mitochondrial inheritance: diverse patterns and mechanisms with an emphasis on fungi

In eukaryotic cells, mitochondria play essential roles by generating the universal energy currency, adenosine triphosphate (ATP), through oxidative phosphorylation to support cellular activities. Similar to chloroplasts in plants and algae, but unlike other intracellular organelles, mitochondria contain their own genetic materials. The mitochondrial genes and genomes are inherited differently and independently from that of nuclear genes and genomes. While uniparental (and maternal) mitochondrial inheritance is the dominant pattern, there is a surprisingly large diversity of other inheritance modes, especially in fungi. Closely related species, or even different strains of the same species, can have different mitochondrial inheritance patterns in the fungal world. In this review, we describe the diversity of mitochondrial DNA inheritance patterns with an emphasis on fungi. Whenever possible, the mitochondrial inheritance patterns observed in fungi are compared with those in other eukaryotes to draw general conclusions about the mechanisms of mitochondrial inheritance in eukaryotes. The inheritance patterns derived from both laboratory crosses and natural populations are reviewed. In addition, we discuss the potential roles of hybridization on mitochondrial inheritance.

Clinicopathologic Characterization of Naturally Occurring Diabetes Mellitus in Vervet Monkeys

Diabetes mellitus (DM) is a group of chronic metabolic diseases characterized by persistent fasting hyperglycemia, and it can be of either polygenic or monogenic origin. Animal models have played an important role in elucidating the pathophysiology of the polygenic Type 1 and type 2 DM forms; however, useful animal models of the monogenic forms do not exist. The authors describe 4 cases of naturally occurring DM in vervet monkeys (Chlorocebus aethiops sabaeus), 1 of which has clinicopathologic findings consistent with type 2 DM, including persistent hyperglycemia, hypertriglyceridemia, islet amyloidosis, and reduced islet insulin immunostaining. In contrast, the 3 remaining animals have clinicopathologic similarities to a monogenic form of the disease, including a lack of islet amyloidosis and hypertriglyceridemia, as well as normal islet insulin immunostaining. In addition, pedigree analysis conducted on one of these animals is consistent with either an autosomal dominant or mitochondrial inheritance pattern, which supports a monogenic form of DM. The authors thus hypothesize that a naturally occurring monogenic form of diabetes may occur in vervet monkeys, making them a potential animal model for future studies.

The mating type-specific homeodomain genes SXI1α and SXI2a coordinately control uniparental mitochondrial inheritance in Cryptococcus neoformans

In the great majority of sexual eukaryotes, mitochondrial genomes are inherited almost exclusively from a single parent. While many hypotheses have been proposed to explain this phenomenon, very little is known about the genetic elements controlling uniparental mitochondria inheritance. In the bipolar, isogamous basidiomycete yeast Cryptococcus neoformans, progeny from crosses between strains of mating type a (MATa) and mating type alpha (MATalpha) typically inherit mitochondrial DNA (mtDNA) from the MATa parent. We recently demonstrated that a mating type alpha (MATalpha)-specific gene SXI1a, controls mitochondrial inheritance in C. neoformans. Here, we show that another homeodomain gene SXI2a in the alternative mating type MATa is also required for uniparental mtDNA inheritance in this fungus. Disruption of SXI2a resulted in biparental mtDNA inheritance in the zygote population with significant numbers of progeny inheriting mtDNA from the MATa parent, the MATalpha parent, and both the MATa and the MATalpha parents. In addition, progeny from same-sex mating between MATalpha strains showed a biparental mitochondrial inheritance pattern. Our results suggest that SXI1alpha and SXI2a coordinately control uniparental mitochondrial inheritance in C. neoformans.

Mitochondrial inheritance patterns in Didymium iridis are not influenced by stage of mating competency

To test whether the timing of transition to mating competency affected mitochondrial transmission patterns in D. iridis. Reciprocal crosses were made by combining mating compatible strains that differed in their competency to mate. The results were compared to crosses where both mating strains were competent at the time of combining and crosses where somatic fusion of plasmodia was allowed. The results show that the mating competency of the parental strains at the time of confronting a compatible mate does not affect mitochondrial transmission patterns, mating efficiency or the likelihood of biparental inheritance. However the timing of plasmodial formation is delayed when precompetent and competent strains are mated compared to when both strains are competent at the time of mixing. We also observed that somatic fusion of plasmodia did not appreciably increase the incidence of biparental inheritance compared to crosses where individual plasmodia were isolated. These results provide additional evidence of the variable nature of mitochondrial inheritance in D. iridis within crosses and between mating trials.

Mitochondrial inheritance patterns in Didymium iridis are not influenced by stage of mating competency

To test whether the timing of transition to mating competency affected mitochondrial transmission patterns in D. iridis. Reciprocal crosses were made by combining mating compatible strains that differed in their competency to mate. The results were compared to crosses where both mating strains were competent at the time of combining and crosses where somatic fusion of plasmodia was allowed. The results show that the mating competency of the parental strains at the time of confronting a compatible mate does not affect mitochondrial transmission patterns, mating efficiency or the likelihood of biparental inheritance. However the timing of plasmodial formation is delayed when precompetent and competent strains are mated compared to when both strains are competent at the time of mixing. We also observed that somatic fusion of plasmodia did not appreciably increase the incidence of biparental inheritance compared to crosses where individual plasmodia were isolated. These results provide additional evidence of the variable nature of mitochondrial inheritance in D. iridis within crosses and between mating trials.

Patterns of mitochondrial inheritance in the myxogastrid Didymium iridis

Seven strains of the Central American A1 mating series of Didymium iridis were crossed in all possible combinations. Individual plasmodia were isolated and grown to a stage where total DNA could be isolated for DNA-DNA hybridization with cloned mitochondrial DNA probes to determine the pattern of mitochondrial inheritance. Random, biased, and dominant patterns of uniparental mitochondrial inheritance were observed, as well as rare cases of biparental inheritance, depending on the particular parental strains mated. The diverse patterns suggest that the factors controlling mitochondrial inheritance in D. iridis are complex. Differences between trials of the same matings suggest that non-genetic factors may also influence mitochondrial inheritance.

Genetics of isolated and syndromic strabismus: Facts and perspectives

Family studies have demonstrated the genetic etiology of concomitant strabismus (prevalence in different populations 1–5%, positive family history in 37% on average), as have twin studies (mean concordance in monozygous twins 73% compared to 35% in dizygous twins). In Duane's syndrome, three chromosomal loci have been identified to date: 2q31, 8q13, and 22q11; loci have also been identified in Moebius syndrome (various inheritance patterns): 13q12.2–q13, 3q21–q22, and 10q21.3–q22, as well as in congenital fibrosis of the extraocular muscles (CFEOM; 3 loci, 1 gene).¹ Already identified are the genes for a number of rarer muscular dystrophy syndromes with ocular involvement, various forms of congenital myasthenia, and mitochondrial diseases (with the primary defect located either in the mtDNA, resulting in a mitochondrial inheritance pattern, or in the nuclear DNA with Mendelian inheritance). A number of hereditary retinal diseases (Mendelian inheritance) may also be associated with strabismus. More than one gene is likely to be involved in the frequently occurring concomitant strabismus, making the analysis more difficult. Patients with chromosomal rearrangements, large families and isolated populations (see also the contributions by Preising and Zitzlsperger et al. in this issue)²,³ will be instrumental in gene identification. In view of the high prevalence of concomitant strabismus, the disclosure of its etiology will have considerable medical, psychosocial and health-cost impact.