Mitochondrial Inheritance Research Articles

Footprints of unconventional mitochondrial inheritance in bivalve phylogeny: Signatures of positive selection on clades with doubly uniparental inheritance

Footprints of unconventional mitochondrial inheritance in bivalve phylogeny: Signatures of positive selection on clades with doubly uniparental inheritance

Compound pathogenic mutation in the USH2A gene in Chinese RP families detected by whole‑exome sequencing.

Retinitis pigmentosa (RP) is a common form of inherited retinal degeneration that causes progressive loss of vision or adult blindness, characterized by the impairment of rod and cone photoreceptors. At present, mutations in >60 pathogenic genes have been confirmed to cause RP. The predominant modes of inheritance are autosomal dominant, autosomal recessive and X-linked. In addition, other modes of inheritance, including digenic or mitochondrial inheritance, have been reported. In previous decades, with the development of sequencing techniques, significant advances in identifying novel RP pathogenic genes and screening mutations have been made. In the present study, whole-exome sequencing was performed on samples from two Chinese pedigrees diagnosed with RP. A compound heterozygous mutation in the gene usherin 2A (USH2A; c.6,485+5G>A/c.11,156G>A) and a heterozygous X-linked mutation in the gene retinitis pigmentosa 2 (RP2) ARL3 GTPase-activating protein (RP2; c.358C>T) were identified by Sanger sequencing and co-segregation analysis, of which the pathogenic mutation (c.6,485+5G>A) in USH2A has not been previously reported among Chinese patients. The findings of the present study may expand on current knowledge of RP among the Chinese population, providing essential assistance in the molecular diagnosis and screening of RP, and promoting further investigation of the pathogenesis of RP.

Failure is not an option - mitochondrial genome segregation in trypanosomes.

Unlike most other model eukaryotes, Trypanosoma brucei and its relatives have a single mitochondrion with a single-unit mitochondrial genome that is termed kinetoplast DNA (kDNA). Replication of the kDNA is coordinated with the cell cycle. During binary mitochondrial fission and prior to cytokinesis, the replicated kDNA has to be faithfully segregated to the daughter organelles. This process depends on the tripartite attachment complex (TAC) that physically links the kDNA across the two mitochondrial membranes with the basal body of the flagellum. Thus, the TAC couples segregation of the replicated kDNA with segregation of the basal bodies of the old and the new flagellum. In this Review, we provide an overview of the role of the TAC in kDNA inheritance in T. brucei We focus on recent advances regarding the molecular composition of the TAC, and discuss how the TAC is assembled and how its subunits are targeted to their respective TAC subdomains. Finally, we will contrast the segregation of the single-unit kDNA in trypanosomes to mitochondrial genome inheritance in yeast and mammals, both of which have numerous mitochondria that each contain multiple genomes.

Fungal mitochondrial genomes and genetic polymorphisms.

Mitochondria are the powerhouses of eukaryotic cells, responsible for ATP generation and playing a role in a diversity of cellular and organismal functions. Different from the majority of other intracellular membrane structures, mitochondria contain their own genetic materials that are capable of independent replication and inheritance. In this mini-review, we provide brief summaries of fungal mitochondrial genome structure, size, gene content, inheritance, and genetic variation. We pay special attention to the relative genetic polymorphisms of the mitochondrial vs nuclear genomes at the population level within individual fungal species. Among the 20 species/groups of species reviewed here, there is a range of variation among genes and species in the relative nuclear and mitochondrial genetic polymorphisms. Interestingly, most (15/20) showed a greater genetic diversity for nuclear genes and genomes than for mitochondrial genes and genomes, with the remaining five showing similar or slower nuclear genome genetic variations. This fungal pattern is different from the dominant pattern in animals, but more similar to that in plants. At present, the mechanisms for the variations among fungal species and the overall low level of mitochondrial sequence polymorphisms are not known. The increasing availability of population genomic data should help us reveal the potential genetic and ecological factors responsible for the observed variations.

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.

Mitochondria-cytosol-nucleus crosstalk: learning from Saccharomyces cerevisiae.

Mitochondria are key cell organelles with a prominent role in both energetic metabolism and the maintenance of cellular homeostasis. Since mitochondria harbor their own genome, which encodes a limited number of proteins critical for oxidative phosphorylation and protein translation, their function and biogenesis strictly depend upon nuclear control. The yeast Saccharomyces cerevisiae has been a unique model for understanding mitochondrial DNA organization and inheritance as well as for deciphering the process of assembly of mitochondrial components. In the last three decades, yeast also provided a powerful tool for unveiling the communication network that coordinates the functions of the nucleus, the cytosol and mitochondria. This crosstalk regulates how cells respond to extra- and intracellular changes either to maintain cellular homeostasis or to activate cell death. This review is focused on the key pathways that mediate nucleus-cytosol-mitochondria communications through both transcriptional regulation and proteostatic signaling. We aim to highlight yeast that likely continues to serve as a productive model organism for mitochondrial research in the years to come.

Direct membrane binding and self-interaction contribute to Mmr1 function in mitochondrial inheritance.

Mitochondrial transport and anchoring mechanisms work in concert to position mitochondria to meet cellular needs. In yeast, Mmr1 functions as a mitochondrial adaptor for Myo2 to facilitate actin-based transport of mitochondria to the bud. Posttransport, Mmr1 is proposed to anchor mitochondria at the bud tip. Although both functions require an interaction between Mmr1 and mitochondria, the molecular basis of the Mmr1–mitochondria interaction is poorly understood. Our in vitro phospholipid binding assays indicate Mmr1 can directly interact with phospholipid membranes. Through structure–function studies we identified an unpredicted membrane-binding domain composed of amino acids 76–195 that is both necessary and sufficient for Mmr1 to interact with mitochondria in vivo and liposomes in vitro. In addition, our structure–function analyses indicate that the coiled-coil domain of Mmr1 is necessary and sufficient for Mmr1 self-interaction and facilitates the polarized localization of the protein. Disrupting either the Mmr1–membrane interaction or Mmr1 self-interaction leads to defects in mitochondrial inheritance. Therefore, direct membrane binding and self-interaction are necessary for Mmr1 function in mitochondrial inheritance and are utilized as a means to spatially and temporally regulate mitochondrial positioning.

Deletion of the sex-determining gene SXI1\u03b1 enhances the spread of mitochondrial introns in Cryptococcus neoformans

BackgroundHoming endonuclease genes (HEGs) are widely distributed genetic elements in the mitochondrial genomes of a diversity of eukaryotes. Due to their ability to self-propagate within and between genomes, these elements can spread rapidly in populations. Whether and how such elements are controlled in genomes remains largely unknown.ResultsHere we report that the HEG-containing introns in the mitochondrial COX1 gene in Cryptococcus neoformans are mobile and that their spread in sexual crosses is influenced by mating type (MAT) α-specific homeodomain gene SXI1α. C. neoformans has two mating types, MATa and MATα. In typical crosses between strains of the two mating types, only a small portion (< 7%) of diploid fusants inherited the HEGs from the MATα parent. However, disruption of the SXI1α gene resulted in the majority (> 95%) of the diploid fusants inheriting the HEG-containing introns from the MATα parent, a frequency significantly higher than those of intronless mitochondrial genes.ConclusionsOur results suggest that SXI1α not only determines uniparental mitochondrial inheritance but also inhibits the spread of HEG-containing introns in the mitochondrial genome in C. neoformans.

Abstract 431: Mitochondrial-nuclear crosstalk influences accumulation of mitochondrial DNA mutations in mammary tumor progression

Abstract Introduction: Previous studies demonstrated that mitochondrial inheritance may contribute to aggressiveness of metastatic disease. Accumulating evidence suggests the mitochondrial genetic background may influence how certain cancers behave. We utilized Mitochondrial-Nuclear eXchange (MNX) female mice crossed with transgenic mice over-expressing the Her-2 gene and showed mitochondrial DNA (mtDNA)-dependent differences in tumor latency, lung metastasis number and lung metastasis size. We hypothesized that mtDNA mutations accumulate as mammary tumors progress and that the evolution is associated with mtDNA-nuclear DNA cross-talk. To test this hypothesis, we conducted next generation sequencing analyses to examine the spectra of mutations in the mitochondrial genome. Methods: Normal mammary gland, primary tumor and lung metastases [n=5 each] were obtained from FVB/NJ mice with FVB/NJ (designated FF), C57BL/6J (designated FC) or BALB/cJ mtDNA (designated FB). Epithelial cells from mammary gland or tumor cells were carefully isolated by laser capture microdissection in order to minimize contamination from surrounding stromal cell mtDNA. mtDNA was deep sequenced using three pools totaling 182 overlapping primers spanning the whole mitochondrial genome using the Ion TorrentTM PGM System. Sequences were compared to an FVB mtDNA reference sequence to detect variants. Results: Significant differences in the total number of mtDNA mutations were observed between the wild-type and MNX mice. Both FB and FC MNX cohorts exhibited increased mtDNA mutations compared to the wild-type (FF). As tumor progressed, the numbers of and distribution of mutations across the mitochondrial genome increased. ‘Hotspots' were observed in FB mice (S12 rRNA, COX I, ND4, CYTB) that were distinct from common mutations in the FC mice (16S rRNA, COX I). Discussion: As predicted, tumor cells accumulated more mutations in mtDNA as neoplastic cells from the primary tumor progressed to metastasis. Surprisingly, wild-type (FF) mice, even though more clinically aggressive (i.e., more metastases), accumulated fewer mtDNA mutations than tumors arising in the MNX mice. The mutations appear to occur in different sites, depending upon the nuclear-mitochondrial combination. Whether the mtDNA mutations function as contributors to metastatic efficiency has not yet been determined. Nonetheless, the data imply that nuclear-mitochondrial cross-talk influences mtDNA mutational spectra and metastasis and that defining the critical mtDNA genes most commonly involved may eventually be used to predict patient prognosis. Citation Format: Takae M. Brewer, Amanda E. Brinker, Sharon Manley, Carolyn J. Vivian, Danny R. Welch. Mitochondrial-nuclear crosstalk influences accumulation of mitochondrial DNA mutations in mammary tumor progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 431.

Genome Survey of the Freshwater Mussel Venustaconcha ellipsiformis (Bivalvia: Unionida) Using a Hybrid De Novo Assembly Approach.

Freshwater mussels (Bivalvia: Unionida) serve an important role as aquatic ecosystem engineers but are one of the most critically imperilled groups of animals. Here, we used a combination of sequencing strategies to assemble and annotate a draft genome of Venustaconcha ellipsiformis, which will serve as a valuable genomic resource given the ecological value and unique “doubly uniparental inheritance” mode of mitochondrial DNA transmission of freshwater mussels. The genome described here was obtained by combining high-coverage short reads (65× genome coverage of Illumina paired-end and 11× genome coverage of mate-pairs sequences) with low-coverage Pacific Biosciences long reads (0.3× genome coverage). Briefly, the final scaffold assembly accounted for a total size of 1.54 Gb (366,926 scaffolds, N50 = 6.5 kb, with 2.3% of “N” nucleotides), representing 86% of the predicted genome size of 1.80 Gb, while over one third of the genome (37.5%) consisted of repeated elements and >85% of the core eukaryotic genes were recovered. Given the repeated genetic bottlenecks of V. ellipsiformis populations as a result of glaciations events, heterozygosity was also found to be remarkably low (0.6%), in contrast to most other sequenced bivalve species. Finally, we reassembled the full mitochondrial genome and found six polymorphic sites with respect to the previously published reference. This resource opens the way to comparative genomics studies to identify genes related to the unique adaptations of freshwater mussels and their distinctive mitochondrial inheritance mechanism.

Mammalian cell-free system for the study of mitochondria inheritance

Mammalian cell-free system for the study of mitochondria inheritance

Structural basis of mitochondrial receptor binding and constriction by DRP1.

SummaryMitochondrial inheritance, genome maintenance, and metabolic adaptation depend on organelle fission by Dynamin-Related Protein 1 (DRP1) and its mitochondrial receptors. DRP1 receptors include the paralogs Mitochondrial Dynamics 49 and 51 (MID49/MID51) and Mitochondrial Fission Factor (MFF), but the mechanisms by which these proteins recruit and regulate DRP1 are unknown. Here we present a cryoEM structure of human, full-length DRP1 coassembled with MID49 and an analysis of structure- and disease-based mutations. We report that GTP induces a remarkable elongation and rotation of the G-domain, Bundle-Signaling Element (BSE) and connecting hinge loops of DRP1. In this conformation, a network of multivalent interactions promotes polymerization of a linear DRP1 filament with MID49/MID51. Following coassembly, GTP hydrolysis and exchange lead to MID receptor dissociation, filament shortening and curling of DRP1 oligomers into constricted and closed rings. Together, these views of full-length, receptor- and nucleotide-bound conformations reveal how DRP1 performs mechanical work through nucleotide-driven allostery.

Influence of Maternal Aging on Mitochondrial Heterogeneity, Inheritance, and Function in Oocytes and Preimplantation Embryos.

Contrasting the equal contribution of nuclear genetic material from maternal and paternal sources to offspring, passage of mitochondria, and thus mitochondrial DNA (mtDNA), is uniparental through the egg. Since mitochondria in eggs are ancestral to all somatic mitochondria of the next generation and to all cells of future generations, oocytes must prepare for the high energetic demands of maturation, fertilization and embryogenesis while simultaneously ensuring that their mitochondrial genomes are inherited in an undamaged state. Although significant effort has been made to understand how the mtDNA bottleneck and purifying selection act coordinately to prevent silent and unchecked spreading of invisible mtDNA mutations through the female germ line across successive generations, it is unknown if and how somatic cells of the immediate next generation are spared from inheritance of detrimental mtDNA molecules. Here, we review unique aspects of mitochondrial activity and segregation in eggs and early embryos, and how these events play into embryonic developmental competency in the face of advancing maternal age.

The role of mitochondria in the female germline: Implications to fertility and inheritance of mitochondrial diseases.

Mitochondria play a fundamental role during development of the female germline. They are fragmented, round, and small. Despite these characteristics suggesting that they are inactive, there is accumulating evidence that mitochondrial dysfunctions are a major cause of infertility and generation of aneuploidies in humans. In addition, mitochondria and their own genomes (mitochondrial DNA-mtDNA) may become damaged with time, which might be one reason why aging leads to infertility. As a result, mitochondria have been proposed as an important target for evaluating oocyte and embryo quality, and developing treatments for female infertility. On the other hand, mutations in mtDNA may cause mitochondrial dysfunctions, leading to severe diseases that affect 1 in 4,300 people. Moreover, very low levels of mutated mtDNA seem to be present in every person worldwide. These may increase with time and associate with late-onset degenerative diseases such as Parkinson disease, Alzheimer disease, and common cancers. Mutations in mtDNA are transmitted down the maternal lineage, following a poorly understood pattern of inheritance. Recent findings have indicated existence in the female germline of a purifying filter against deleterious mtDNA variants. Although the underlying mechanism of this filter is largely unknown, it has been suggested to rely on autophagic degradation of dysfunctional mitochondria or selective replication/transmission of non-deleterious variants. Thus, understanding the mechanisms regulating mitochondrial inheritance is important both to improve diagnosis and develop therapeutic tools for preventing transmission of mtDNA-encoded diseases.

Response to Ghiselli F et al. (2018).

I thank the authors (Ghiselli et al . [1]) for their interesting comments regarding my article [2]. They indeed further clarified some important points regarding both uniparental organelle inheritance (UPI), which we encounter almost exclusively as strictly maternal inheritance (SMI) and doubly uniparental inheritance (DUI) as well as ‘role-reversal' of F-type mitochondrial DNA (mtDNA). Their data again illustrate the fascinating variety in mitochondrial inheritance. The authors critically discuss their data to ask whether these support John Allen's ‘division of labour' hypothesis [3], where male gametes maximize energy production for competitive advantages in motility, thus damaging mtDNA by mutagenic reactive oxygen species (ROS), coming from oxidative phosphorylation (OXPHOS). Non-motile female gametes, on the other hand, repress OXPHOS, keeping their mtDNA pristine. They ‘clarify two discussion points: (i) the exceptions to the strictly maternal inheritance (SMI) of mitochondria and (ii) the claim that mtDNA is highly mutated in sperm and the supposed causal relationship between such damage and OXPHOS.' Before responding to their arguments, it is worthwhile to very briefly summarize a possible …

Mitochondrial activity in gametes and uniparental inheritance: a comment on 'What can we infer about the origin of sex in early eukaryotes?'

In his insightful article, Speijer [1] discussed the origin of sex under multiple points of view, providing a comprehensive and balanced overview of different theories and hypotheses. However, we think that the section ‘Higher mutational loads in one gamete type and retention of uniparental mitochondrial inheritance’ (§9) needs some clarification. Speijer [1] elaborates on the correlation between gamete metabolic and physiological differences and their organellar contribution across generations. Specifically, he quotes the ‘division of labour’ hypothesis, which postulates that male gametes maximize energy production for motility by sacrificing mitochondrial DNA (mtDNA) to oxidative phosphorylation (OXPHOS) and its mutagenic by-products, while non-motile female gametes repress OXPHOS, thus being somewhat inactive [2]. Basically, we clarify two discussion points: (i) the exceptions to the strictly maternal inheritance (SMI) of mitochondria and (ii) the claim that mtDNA is highly mutated in sperm and the supposed causal relationship between such damage and OXPHOS. Exceptions to SMI by which bioenergetically active mitochondria are stably inherited through generations might represent a challenge for the division of labour hypothesis. Doubly uniparental inheritance (DUI) is the only known evolutionarily stable exception to the SMI typical of Metazoa. In DUI animals (approx. 100 species of gonochoric bivalve molluscs identified so far [3]), two mitochondrial lineages are inherited, one through eggs (F-type) and the other through sperm (M-type). Eggs are homoplasmic for the F-type, while spermatozoa are homoplasmic for the M-type. These ‘mother-to-daughter’ and ‘father-to-son’ mitochondrial lineages have evolved independently for millions of years (e.g. more than 200 Myr in unionids), accumulating up to 40% of DNA sequence divergence. Since eggs do not transmit the M-type, germ line mitochondria of DUI males are apportioned from the four/five mitochondria of the fertilizing spermatozoon, which carry mtDNA that must be functional and successfully inherited [ …

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.

Mitochondrial Morphology Controls Hematopoietic Stem Cell Self-Renewal and Confers Them Divisional Memory

Hematopoietic stem cells (HSC) have extensive regenerative potential but limited self-renewal ability. The repopulation potential is gradually lost with HSC divisions and during stress hematopoiesis. Hence, we hypothesize that activation or inactivation of signaling pathways or other mechanisms, inherently occurring during HSC activation into cycle, drives their progressive functional decline. To address this, we used single cell RNA-sequencing and compared the transcriptome of HSCs [Lin-c-Kit+Sca-1+CD48-CD150+] that is expressed upon exit from quiescence and the one that is inherited by daughter cells upon HSC division. We compared HSCs with full self-renewal activity to HSCs that have lost self-renewal activity [i.e. before (NT-HSC) and after transplantation (T-HSC), respectively]. Analysis of the data was performed using unsupervised methods, namely iterative clustering and guide-gene selection (ICGS), [Olsson et al, Nature, 2016] and principal component (PCA) analysis. Each revealed that genes categorized in mitochondrial organization were dramatically upregulated in activated NT-HSC and remained highly expressed in their daughter cells. Remarkably, ICGS revealed at least 2 distinct regulatory states within T-HSC; one that clustered within NT-HSC, and another one that was clearly separated from NT-HSC. The latter was exclusively comprised of daughter T-HSCs, and quite unexpectedly was demarcated by a lack of expression of mitochondrial genes along with changes in expression of genes related to cytoskeleton organization. Using EGFP-mitochondria reporter mice; which labels mitochondria regardless of their membrane potential and activated state, we found that NT-HSC had 4-fold higher mitochondrial content than progenitors. High resolution confocal imaging indicated that mitochondria were punctuated and the network was dispersed in the entire cell volume in NT-HSC. However, in T-HSCs, mitochondria formed one or a few larger aggregates. Mitochondrial membrane potential was also severely reduced in T-HSC in vivo, indicating that HSC accumulate dysfunctional mitochondria after replicative stress during stress hematopoiesis. During cell division, in vitro, mitochondria were unequally distributed to daughter cells of single T-HSC division [one daughter cell had more aggregated mitochondria], whereas mitochondria were equally partitioned during division of NT-HSC, suggesting that HSC lose mitochondrial quality control after replicative stress. Further, mitochondria aligned along the microtubule network in NT-HSC but not in T-HSC. Mitochondrial morphology and distribution are maintained through regulated cycles of fission and fusion, which is essential for maintaining a functional organelle and for equal mitochondrial inheritance during division. We found that the mitochondrial fission protein Drp1, which normally accumulated and wrapped around mitochondria in NT-HSC during cell activation, failed to do so in T-HSCs, perhaps due to impaired mitochondrial-cytoskeleton association. Genetic loss of Drp1 caused severe mitochondrial aggregation in HSCs, and impaired HSC self-renewal and repopulation ability in competitive transplant studies, indicating that accumulation of aggregated and dysfunctional mitochondria causes HSC functional defects. To understand whether HSCs accumulated abnormal mitochondrial morphology with divisional history during homeostatic conditions, we used the GFP label-retaining H2B mouse model. Remarkably, mitochondria were well dispersed and homogeneously distributed in GFP labeled-retaining HSCs (i.e. HSC that had not divided), while HSCs with history of cell division (no GFP) had larger and more compact aggregates. Hence, once HSCs exit from quiescence, they irreversibly accumulate dysfunctional mitochondria over the course of divisions due to lack of mitochondrial quality control mechanisms, which drives gradual heterogeneity and loss of self-renewal ability. Thus, HSCs use mitochondrial architecture to remember their divisions, in turn affecting their self-renewal ability. Therefore, drugs or pharmacological inhibitors targeting mitochondrial organization or its quality can be new therapeutic approach to improve HSC function following transplantation. DisclosuresNo relevant conflicts of interest to declare.

Post-fertilisation sperm mitophagy: the tale of Mitochondrial Eve and Steve.

Preformationist William Harvey's proclamation of everything live coming from an egg still holds true for mammalian mitochondria and mitochondrial genes. At fertilisation, mitochondria carried into the oocyte cytoplasm by the spermatozoon are sought out and destroyed, leaving only oocyte mitochondria to propagate their mitochondrial (mt) DNA to offspring. This clonal inheritance mode, the 'mitochondrial Eve' paradigm, is mediated by oocytes' resident proteolytic, organelle-targeting mechanisms, including the substrate-specific ubiquitin proteasome system and the autophagic machinery for bulk protein and organelle degradation. Ubiquitination of sperm mitochondria within the cytoplasm of the fertilised oocyte was initially discovered in mammals. More recent studies in Drosophila and Caenorhabditis elegans implicated the ubiquitin-binding autophagy protein sequestosome 1 (SQSTM1) as the early adaptor channelling ubiquitinated sperm mitochondria towards the autophagic machinery. Downstream receptors include microtubule-associated protein 1 light chain 3α (LC3) and GABA type A receptor-associated protein (GABARAP). Among mammals, the domestic pig is the ideal mammalian model of mitochondrial inheritance because of rapid sperm mitophagy at the 1-cell stage of embryo development. Primary recognition of sperm mitochondria by SQSTM1 inside the porcine zygote is followed by GABARAP-containing autophagophore formation, and contributed to by valosin-containing protein (VCP), a 26S proteasome-presenting protein dislocase. Consequently, coinhibition of SQSTM1-GABARAP and VCP activities in the porcine zygotes, resulting in 2- to 4-cell embryos carrying intact sperm mitochondrial sheaths, revived the moniker of 'Mitochondrial Steve'. Further work will identify the determinants of species specificity of sperm mitophagy and explain the interplay and possible consequences of a mismatch between clonal mitochondrial genome and biparentally inherited chromosomal genes encoding for structural mitochondrial proteins and transcription factors. By better understanding sperm mitophagy and its potential failure, we may be able to alleviate mitochondrial disease and early pregnancy loss in livestock and improve their fitness, reproduction and ability to pass favourable production traits to offspring.

Sexual conflict explains the extraordinary diversity of mechanisms regulating mitochondrial inheritance

BackgroundMitochondria are predominantly inherited from the maternal gamete, even in unicellular organisms. Yet an extraordinary array of mechanisms enforce uniparental inheritance, which implies shifting selection pressures and multiple origins.ResultsWe consider how this high turnover in mechanisms controlling uniparental inheritance arises using a novel evolutionary model in which control of mitochondrial transmission occurs either during spermatogenesis (by paternal nuclear genes) or at/after fertilization (by maternal nuclear genes). The model treats paternal leakage as an evolvable trait. Our evolutionary analysis shows that maternal control consistently favours strict uniparental inheritance with complete exclusion of sperm mitochondria, whereas some degree of paternal leakage of mitochondria is an expected outcome under paternal control. This difference arises because mito-nuclear linkage builds up with maternal control, allowing the greater variance created by asymmetric inheritance to boost the efficiency of purifying selection and bring benefits in the long term. In contrast, under paternal control, mito-nuclear linkage tends to be much weaker, giving greater advantage to the mixing of cytotypes, which improves mean fitness in the short term, even though it imposes a fitness cost to both mating types in the long term.ConclusionsSexual conflict is an inevitable outcome when there is competition between maternal and paternal control of mitochondrial inheritance. If evolution has led to complete uniparental inheritance through maternal control, it creates selective pressure on the paternal nucleus in favour of subversion through paternal leakage, and vice versa. This selective divergence provides a reason for the repeated evolution of novel mechanisms that regulate the transmission of paternal mitochondria, both in the fertilized egg and spermatogenesis. Our analysis suggests that the widespread occurrence of paternal leakage and prevalence of heteroplasmy are natural outcomes of this sexual conflict.