Mitochondrial Variation in Anopheles gambiae and Anopheles coluzzii: Phylogeographic Legacy and Mitonuclear Associations With Metabolic Resistance to Pathogens and Insecticides.

Mitochondrial DNA has been a popular marker in phylogeography, phylogeny, and molecular ecology, but its complex evolution is increasingly recognized. Here, we investigated mitochondrial DNA variation in Anopheles gambiae and Anopheles coluzzii, in relation to other species in the Anopheles gambiae complex, by assembling the mitogenomes of 1,219 mosquitoes across Africa. The mitochondrial DNA phylogeny of the Anopheles gambiae complex was consistent with previously reported highly reticulated evolutionary history, revealing important discordances with the species tree. The three most widespread species (An. gambiae, An. coluzzii, and Anopheles arabiensis), known for extensive historical introgression, could not be discriminated based on mitogenomes. Furthermore, a monophyletic clustering of the three saltwater-tolerant species (Anopheles merus, Anopheles melas, and Anopheles bwambae) in the Anopheles gambiae complex also suggested that introgression and possibly selection shaped mitochondrial DNA evolution. Mitochondrial DNA variation in An. gambiae and An. coluzzii across Africa revealed significant partitioning among populations and species. A peculiar mitochondrial DNA lineage found predominantly in An. coluzzii and in the hybrid taxon of the African "far-west" exhibited divergence comparable to the interspecies divergence in the Anopheles gambiae complex, with a geographic distribution matching closely An. coluzzii's geographic range. This phylogeographic relict of the An. coluzzii and An. gambiae split was associated with population and species structure, but not with the rare Wolbachia occurrence. The lineage was significantly associated with single nucleotide polymorphisms in the nuclear genome, particularly in genes associated with pathogen and insecticide resistance. These findings underline potential mitonuclear coevolution history and the role played by mitochondria in shaping metabolic responses to pathogens and insecticides in Anopheles.

Rapamycin's lifespan effect is modulated by mito-nuclear epistasis in Drosophila.

The macrolide drug rapamycin is a benchmark anti-ageing drug, which robustly extends lifespan of diverse organisms. For any health intervention, it is paramount to establish whether benefits are distributed equitably among individuals and populations, and ideally to match intervention to recipients' needs. However, how responses to rapamycin vary is surprisingly understudied. Here we investigate how among-population variation in both mitochondrial and nuclear genetics shapes rapamycin's effects on lifespan. We show that epistatic "mito-nuclear" interactions, between mitochondria and nuclei, modulate the response to rapamycin treatment. Differences manifest as differential demographic effects of rapamycin, with altered age-specific mortality rate. However, a fitness cost of rapamycin early in life does not show a correlated response, suggesting that mito-nuclear epistasis can decouple costs and benefits of treatment. These findings suggest that a deeper understanding of how variation in mitochondrial and nuclear genomes shapes physiology may facilitate tailoring of anti-ageing therapy to individual need.

Mitonuclear and phenotypic discordance in an Atlantic Forest frog hybrid zone.

Discordance between mitochondrial and nuclear DNA is common among animals and can be the result of a number of evolutionary processes, including incomplete lineage sorting and introgression. Particularly relevant in contact zones, mitonuclear discordance is expected because the mitochondrial genome is haploid and primarily uniparentally inherited, whereas nuclear loci are evolving at slower rates. In addition, when closely related taxa come together in hybrid zones, the distribution of diagnostic phenotypic characters and their concordance with the mitochondrial or nuclear lineages can also inform on historical and ongoing dynamics within hybrid zones. Overall, genetic and phenotypic discordances provide evidence for evolutionary divergence and processes that maintain boundaries among sister species or lineages. In this study, we characterized patterns of genetic and phenotypic variation in a contact zone between Cycloramphus dubius and Cycloramphus boraceiensis, two sister species of frogs endemic to the Atlantic Coastal Forest of Brazil. We examined genomic-scale nuclear diversification across 19 populations, encompassing the two parental forms and a contact zone between them. We compared the distribution of genomic DNA variability with that of a mitochondrial locus (16S) and two morphological traits (dorsal tubercles and body size). Our results reveal multiple divergent lineages with ongoing admixture. We detected discordance in patterns of introgression across the three data types. Cycloramphus dubius males are significantly larger than C. boraceiensis males, and we posit that competition among males in the hybrid zone, coupled with mate choice by females, may be one mechanism leading to patterns of introgression observed between the species.

The limits of the metapopulation: Lineage fragmentation in a widespread terrestrial salamander (Plethodon cinereus).

In vicariant species formation, divergence results primarily from periods of allopatry and restricted gene flow. Widespread species harboring differentiated, geographically distinct sublineages offer a window into what may be a common mode of species formation, whereby a species originates, spreads across the landscape, then fragments into multiple units. However, incipient lineages usually lack reproductive barriers that prevent their fusion upon secondary contact, blurring the boundaries between a single, large metapopulation-level lineage and multiple independent species. Here we explore this model of species formation in the Eastern Red-backed Salamander (Plethodon cinereus), a widespread terrestrial vertebrate with at least six divergent mitochondrial clades throughout its range. Using anchored hybrid enrichment data, we applied phylogenomic and population genomic approaches to investigate patterns of divergence, gene flow, and secondary contact. Genomic data broadly match most mitochondrial groups but reveal mitochondrial introgression and extensive admixture at several contact zones. While species delimitation analyses in BPP supported five lineages of P. cinereus, genealogical divergence indices (gdi) were highly sensitive to the inclusion of admixed samples and the geographic representation of candidate species, with increasing support for multiple species when removing admixed samples or limiting sampling to a single locality per group. An analysis of morphometric data revealed differences in body size and limb proportions among groups, with a reduction of forelimb length among warmer and drier localities consistent with increased fossoriality. We conclude that P. cinereus is a single species, but one with highly structured component lineages of various degrees of independence.

A consequential one-night stand: Episodic historical hybridization leads to mitochondrial takeover in sympatric desert ant-eating spiders.

Disentangling the genomic intricacies underlying speciation and the causes of discordance between sources of evidence can offer remarkable insights into evolutionary dynamics. The ant-eating spider Zodarion nitidum, found across the Middle East and Egypt, displays yellowish and blackish morphs that co-occur sympatrically. These morphs additionally differ in behavioral and physiological features and show complete pre-mating reproductive isolation. In contrast, they possess similar sexual features and lack distinct differences in their mitochondrial DNA. We analyzed both Z. nitidum morphs and outgroups using genome-wide and additional mitochondrial DNA data. The genomic evidence indicated that Yellow and Black are reciprocally independent lineages without signs of recent admixture. Interestingly, the sister group of Yellow is not Black but Z. luctuosum, a morphologically distinct species. Genomic gene flow analyses pinpointed an asymmetric nuclear introgression event, with Yellow contributing nearly 5 % of its genome to Black roughly 320,000 years ago, intriguingly aligning with the independently estimated origin of the mitochondrial DNA of Black. We conclude that the blackish and yellowish morphs of Z. nitidum are long-diverged distinct species, and that the ancient and modest genomic introgression event registered resulted in a complete mitochondrial takeover of Black by Yellow. This investigation underscores the profound long-term effects that even modest hybridization events can have on the genome of organisms. It also exemplifies the utility of phylogenetic networks for estimating historical events and how integrating independent lines of evidence can increase the reliability of such estimations.

Sex, tissue, and mitochondrial interactions modify the transcriptional response to rapamycin in Drosophila.

BACKGROUND: Many common diseases exhibit uncontrolled mTOR signaling, prompting considerable interest in the therapeutic potential of mTOR inhibitors, such as rapamycin, to treat a range of conditions, including cancer, aging-related pathologies, and neurological disorders. Despite encouraging preclinical results, the success of mTOR interventions in the clinic has been limited by off-target side effects and dose-limiting toxicities. Improving clinical efficacy and mitigating side effects require a better understanding of the influence of key clinical factors, such as sex, tissue, and genomic background, on the outcomes of mTOR-targeting therapies. RESULTS: We assayed gene expression with and without rapamycin exposure across three distinct body parts (head, thorax, abdomen) of D. melanogaster flies, bearing either their native melanogaster mitochondrial genome or the mitochondrial genome from a related species, D. simulans. The fully factorial RNA-seq study design revealed a large number of genes that responded to the rapamycin treatment in a sex-dependent and tissue-dependent manner, and relatively few genes with the transcriptional response to rapamycin affected by the mitochondrial background. Reanalysis of an earlier study confirmed that mitochondria can have a temporal influence on rapamycin response. CONCLUSIONS: We found significant and wide-ranging effects of sex and body part, alongside a subtle, potentially time-dependent, influence of mitochondria on the transcriptional response to rapamycin. Our findings suggest a number of pathways that could be crucial for predicting potential side effects of mTOR inhibition in a particular sex or tissue. Further studies of the temporal response to rapamycin are necessary to elucidate the effects of the mitochondrial background on mTOR and its inhibition.

Accelerated mitochondrial evolution and asymmetric fitness of hybrids contribute to the persistence of Helix thessalica in the Helix pomatia range.

Interbreeding and introgression between recently diverged species is common. However, the processes that prevent these species from merging where they co-occur are not well understood. We studied the mechanisms that allowed an isolated group of populations of the snail Helix thessalica to persist within the range of the related Helix pomatia despite high gene flow. Using genomic cline analysis, we found that the nuclear gene flow between the two taxa across the mosaic hybrid zone was not different from that expected under neutral admixture, but that the exchange of mtDNA was asymmetric. Tests showed that there is relaxed selection in the mitochondrial genome of H. thessalica and that the substitution rate is elevated compared to that of H. pomatia. A lack of hybrids that combine the mtDNA of H. thessalica with a mainly (>46%) H. pomatia genomic background indicates that the nuclear-encoded mitochondrial proteins of H. pomatia are not well adapted to the more rapidly evolving proteins and RNAs encoded by the mitochondrion of H. thessalica. The presumed reduction of fitness of hybrids with the fast-evolving mtDNA of H. thessalica and a high H. pomatia ancestry, similar to 'Darwin's Corollary to Haldane's rule', resulted in a relative loss of H. pomatia nuclear ancestry compared to H. thessalica ancestry in the hybrid zone. This probably prevents the H. thessalica populations from merging quickly with the surrounding H. pomatia populations and supports the hypothesis that incompatibilities between rapidly evolving mitochondrial genes and nuclear genes contribute to speciation.

Mitochondrion-to-nucleus communication mediated by RNA export: a survey of potential mechanisms and players across eukaryotes.

The nucleus interacts with the other organelles to perform essential functions of the eukaryotic cell. Mitochondria have their own genome and communicate back to the nucleus in what is known as mitochondrial retrograde response. Information is transferred to the nucleus in many ways, leading to wide-ranging changes in nuclear gene expression and culminating with changes in metabolic, regulatory or stress-related pathways. RNAs are emerging molecules involved in this signalling. RNAs encode precise information and are involved in highly target-specific signalling, through a wide range of processes known as RNA interference. RNA-mediated mitochondrial retrograde response requires these molecules to exit the mitochondrion, a process that is still mostly unknown. We suggest that the proteins/complexes translocases of the inner membrane, polynucleotide phosphorylase, mitochondrial permeability transition pore, and the subunits of oxidative phosphorylation complexes may be responsible for RNA export.

Interconnected roles of fungal nuclear- and intron-encoded maturases: at the crossroads of mitochondrial intron splicing.

Group I and II introns are large catalytic RNAs (ribozymes) that are frequently encountered in fungal mitochondrial genomes. The discovery of respiratory mutants linked to intron splicing defects demonstrated that for the efficient removal of organellar introns there appears to be a requirement of protein splicing factors. These splicing factors can be intron-encoded proteins with maturase activities that usually promote the splicing of the introns that encode them (cis-acting) and/or nuclear-encoded factors that can promote the splicing of a range of different introns (trans-acting). Compared to plants organellar introns, fungal mitochondrial intron splicing is still poorly explored, especially in terms of the synergy of nuclear factors with intron-encoded maturases that has direct impact on splicing through their association with intron RNA. In addition, nuclear-encoded accessory factors might drive the splicing impetus through translational activation, mitoribosome assembly, and phosphorylation-mediated RNA turnover. This review explores protein-assisted splicing of introns by nuclear and mitochondrial-encoded maturases as a means of mitonuclear interplay that could respond to environmental and developmental factors promoting phenotypic adaptation and potentially speciation. It also highlights key evolutionary events that have led to changes in structure and ATP-dependence to accommodate the dual functionality of nuclear and organellar splicing factors.

"Isolation by Gentes with Asymmetric Migration" shapes the genetic structure of the common cuckoo in China.

Amid coevolutionary arms races between brood parasitic birds and their diverse host species, the formation of host-specific races, or gentes, has drawn significant research focus. Nevertheless, numerous questions about gentes evolutionary patterns persist. Here, we investigated the potential for gentes evolution across multiple common cuckoo (Cuculus canorus) populations parasitizing diverse host species in China. Using maternal (mitochondrial and W-linked DNA) and biparental (autosomal and Z-linked DNA) markers, we found consistent clustering of cuckoo gentes (rather than geographical populations) into distinct clades in matrilineal gene trees, indicating robust differentiation. In contrast, biparental markers indicated intermixing of all gentes, suggesting asymmetric gene flow regardless of geography. Unlike the mitonuclear discordance commonly resulting from incomplete lineage sorting, adaptive introgression, or demographic disparities, the observed pattern in brood parasitic cuckoos might reflect biased host preferences between sexes. We hereby present the "Isolation by Gentes with Asymmetric Migration" model. According to this model, the maternal line differentiation of the common cuckoo in China is potentially driven by host preferences in females, whereas males maintained the integrity of the cuckoo species through random mating. To achieve this, cuckoo males could perform flexible migration among gentes or engage in early copulation with females before reaching the breeding sites, allowing female cuckoos to store sperm from various gentes. Future studies collecting additional samples from diverse cuckoo gentes with overlapping distribution and investigating the migratory and copulation patterns of each sex would enhance our understanding of sex-biased differentiation among cuckoo populations in China.

Exon capture museomics deciphers the nine-banded armadillo species complex and identifies a new species endemic to the Guiana Shield.

The nine-banded armadillo (Dasypus novemcinctus) is the most widespread xenarthran species across the Americas. Recent studies have suggested it is composed of four morphologically and genetically distinct lineages of uncertain taxonomic status. To address this issue, we used a museomic approach to sequence 80 complete mitogenomes and capture 997 nuclear loci for 71 Dasypus individuals sampled across the entire distribution. We carefully cleaned up potential genotyping errors and cross contaminations that could blur species boundaries by mimicking gene flow. Our results unambiguously support four distinct lineages within the D. novemcinctus complex. We found cases of mito-nuclear phylogenetic discordance but only limited contemporary gene flow confined to the margins of the lineage distributions. All available evidence including the restricted gene flow, phylogenetic reconstructions based on both mitogenomes and nuclear loci, and phylogenetic delimitation methods consistently supported the four lineages within D. novemcinctus as four distinct species. Comparable genetic differentiation values to other recognized Dasypus species further reinforced their status as valid species. Considering congruent morphological results from previous studies, we provide an integrative taxonomic view to recognise four species within the D. novemcinctus complex: D. novemcinctus, D. fenestratus, D. mexicanus, and D. guianensis sp. nov., a new species endemic of the Guiana Shield that we describe here. The two available individuals of D. mazzai and D. sabanicola were consistently nested within D. novemcinctus lineage and their status remains to be assessed. The present work offers a case study illustrating the power of museomics to reveal cryptic species diversity within a widely distributed and emblematic species of mammals.

Integrative taxonomy, phylogenetics and historical biogeography of subgenus Aeschyntelus Stål, 1872 (Hemiptera: Heteroptera: Rhopalidae).

The subgenus Aeschyntelus includes six species that show variations in body color and shape, thus making it difficult to identify them based on morphological identification alone. To date, no genetic study has evaluated species within this genus. Herein, we collected 171 individuals from 90 localities of Rhopalus and employed an integrative taxonomic approach that incorporated morphological data, mitochondrial genomic data (COI, whole mitochondrial data) and nuclear genomic data (18S + 28S rRNAs, nuclear genome-wide SNPs) to delineate species boundaries. Our analyses confirmed the status of nine described species of Rhopalus and proposed the recognition of one new species known as Rhopalus qinlinganus sp. nov., which is classified within the subgenus Aeschyntelus. Discrepancies arising from nuclear and mitochondrial data suggest the presence of mito-nuclear discordance. Specifically, mitochondrial data indicated admixture within Clade A, comprising R. kerzhneri and R. latus, whereas genome-wide SNPs unambiguously identified two separate species, aligning with morphological classification. Conversely, mitochondrial data clearly distinguished Clade B- consisting of R. sapporensis into two lineages, whereas genome-wide SNPs unequivocally identified a single species. Our study also provides insights into the evolutionary history of Aeschyntelus, thus indicating that it likely originated in East Asia during the middle Miocene. The development of Aeschyntelus biodiversity in the southwestern mountains of China occurred via an uplift-driven diversification process. Our findings highlight the necessity of integrating both morphological and multiple molecular datasets for precise species identification, particularly when delineating closely related species. Additionally, it reveals the important role of mountain orogenesis on speciation within the southwestern mountains of China.

Central dogma rates in human mitochondria.

In human cells, the nuclear and mitochondrial genomes engage in a complex interplay to produce dual-encoded oxidative phosphorylation (OXPHOS) complexes. The coordination of these dynamic gene expression processes is essential for producing matched amounts of OXPHOS protein subunits. This review focuses on our current understanding of the mitochondrial central dogma rates, highlighting the striking differences in gene expression rates between mitochondrial and nuclear genes. We synthesize a coherent model of mitochondrial gene expression kinetics, highlighting the emerging principles and emphasizing where more precise measurements would be beneficial. Such an understanding is pivotal for grasping the unique aspects of mitochondrial function and its role in cellular energetics, and it has profound implications for aging, metabolic disorders, and neurodegenerative diseases.

Ancestry affects the transcription of small mitochondrial RNAs in human lymphocytes.

Mitochondrial mutations have been linked to changes in phenotypes such as fertility or longevity, however, these changes have been often inconsistent across populations for unknown reasons. A hypothesis that could explain this inconsistency is that some still uncharacterized mitochondrial products are mediating the phenotypic changes across populations. It has been hypothesized that one such product could be the small RNAs encoded in the mitochondrial genome, thus this work will provide new evidence for their existence and function. By using data from the 1000 genome project and knowledge from previously characterized nuclear small RNAs, this study found that 10 small RNAs encoded in tRNA fragments are consistently expressed in 450 individuals from five different populations. Furthermore, this study demonstrated that the expression of some small mitochondrial RNAs is different in individuals of African ancestry, similar to what was observed before in nuclear and mitochondria mRNAs. Lastly, we investigate the causes behind these differences in expression, showing that at least one of the mt-tRFs might be regulated by TRMT10B. The analyses presented in this work further support the small mitochondrial RNAs as functional molecules, and their population-specific expression supports the hypothesis that they act as a mediator between the nucleus and mitochondria differently across populations.

A G-quadruplex-binding platinum complex induces cancer mitochondrial dysfunction through dual-targeting mitochondrial and nuclear G4 enriched genome.

BACKGROUND: G-quadruplex DNA (G4) is a non-canonical structure forming in guanine-rich regions, which play a vital role in cancer biology and are now being acknowledged in both nuclear and mitochondrial (mt) genome. However, the impact of G4-based targeted therapy on both nuclear and mt genome, affecting mt function and its underlying mechanisms remain largely unexplored. METHODS: The mechanisms of action and therapeutic effects of a G4-binding platinum(II) complex, Pt-ttpy, on mitochondria were conducted through a comprehensive approaches with in vitro and in vivo models, including ICP-MS for platinum measurement, PCR-based genetic analysis, western blotting (WB), confocal microscope for mt morphology study, extracellular flux analyzer, JC1 and Annexin V apoptosis assay, flow cytometry and high content microscope screening with single-cell quantification of both ROS and mt specific ROS, as well as click-chemistry for IF study of mt translation. Decipher Pt-ttpy effects on nuclear-encoded mt related genes expression were undertaken via RNA-seq, Chip-seq and CUT-RUN assays. RESULTS: Pt-ttpy, shows a highest accumulation in the mitochondria of A2780 cancer cells as compared with two other platinum(II) complexes with no/weak G4-binding properties, Pt-tpy and cisplatin. Pt-ttpy induces mtDNA deletion, copy reduction and transcription inhibition, hindering mt protein translation. Functional analysis reveals potent mt dysfunction without reactive oxygen species (ROS) induction. Mechanistic study provided first evidence that most of mt ribosome genes are highly enriched in G4 structures in their promoter regions, notably, Pt-ttpy impairs most nuclear-encoded mt ribosome genes' transcription through dampening the recruiting of transcription initiation and elongation factors of NELFB and TAF1 to their promoter with G4-enriched sequences. In vivo studies show Pt-ttpy's efficient anti-tumor effects, disrupting mt genome function with fewer side effects than cisplatin. CONCLUSION: This study underscores Pt-ttpy as a G4-binding platinum(II) complex, effectively targeting cancer mitochondria through dual action on mt and nuclear G4-enriched genomes without inducing ROS, offering promise for safer and effective platinum-based G4-targeted cancer therapy.

Functional characterization of archaic-specific variants in mitonuclear genes: insights from comparative analysis in S. cerevisiae.

Neanderthal and Denisovan hybridisation with modern humans has generated a non-random genomic distribution of introgressed regions, the result of drift and selection dynamics. Cross-species genomic incompatibility and more efficient removal of slightly deleterious archaic variants have been proposed as selection-based processes involved in the post-hybridisation purge of archaic introgressed regions. Both scenarios require the presence of functionally different alleles across Homo species onto which selection operated differently according to which populations hosted them, but only a few of these variants have been pinpointed so far. In order to identify functionally divergent archaic variants removed in humans, we focused on mitonuclear genes, which are underrepresented in the genomic landscape of archaic humans. We searched for non-synonymous, fixed, archaic-derived variants present in mitonuclear genes, rare or absent in human populations. We then compared the functional impact of archaic and human variants in the model organism Saccharomyces cerevisiae. Notably, a variant within the mitochondrial tyrosyl-tRNA synthetase 2 (YARS2) gene exhibited a significant decrease in respiratory activity and a substantial reduction of Cox2 levels, a proxy for mitochondrial protein biosynthesis, coupled with the accumulation of the YARS2 protein precursor and a lower amount of mature enzyme. Our work suggests that this variant is associated with mitochondrial functionality impairment, thus contributing to the purging of archaic introgression in YARS2. While different molecular mechanisms may have impacted other mitonuclear genes, our approach can be extended to the functional screening of mitonuclear genetic variants present across species and populations.

Wolbachia infection status and molecular diversity in the species of tribe Tagiadini Mabille, 1878 (Lepidoptera: Hesperiidae) collected in China.

Wolbachia, one of the most ubiquitous heritable symbionts in lepidopteran insects, can cause mitochondrial introgression in related host species. We recently found mito-nuclear discordance in the Lepidopteran tribe Tagiadini Mabille 1878 from which Wolbachia has not been reported. In this study, we found that 13 of the 46 species of Tagiadini species tested were positive for Wolbachia. Overall, 14% (15/110) of Tagiadini specimens were infected with Wolbachia and nine new STs were found from 15 isolates. A co-phylogenetic comparison, divergence time estimation and Wolbachia recombination analysis revealed that mito-nuclear discordance in Tagiadini species is not mediated by Wolbachia, but Wolbachia acquisition in Tagiadini appears to have occurred mainly through horizontal transmission rather than codivergence.

Mother's Curse effects on lifespan and aging.

The Mother's Curse hypothesis posits that mothers curse their sons with harmful mitochondria, because maternal mitochondrial inheritance makes selection blind to mitochondrial mutations that harm only males. As a result, mitochondrial function may be evolutionarily optimized for females. This is an attractive explanation for ubiquitous sex differences in lifespan and aging, given the prevalence of maternal mitochondrial inheritance and the established relationship between mitochondria and aging. This review outlines patterns expected under the hypothesis, and traits most likely to be affected, chiefly those that are sexually dimorphic and energy intensive. A survey of the literature shows that evidence for Mother's Curse is limited to a few taxonomic groups, with the strongest support coming from experimental crosses in Drosophila. Much of the evidence comes from studies of fertility, which is expected to be particularly vulnerable to male-harming mitochondrial mutations, but studies of lifespan and aging also show evidence of Mother's Curse effects. Despite some very compelling studies supporting the hypothesis, the evidence is quite patchy overall, with contradictory results even found for the same traits in the same taxa. Reasons for this scarcity of evidence are discussed, including nuclear compensation, factors opposing male-specific mutation load, effects of interspecific hybridization, context dependency and demographic effects. Mother's Curse effects may indeed contribute to sex differences, but the complexity of other contributing factors make Mother's Curse a poor general predictor of sex-specific lifespan and aging.

Conservation Mitonuclear Replacement: Facilitated mitochondrial adaptation for a changing world.

Most species will not be able to migrate fast enough to cope with climate change, nor evolve quickly enough with current levels of genetic variation. Exacerbating the problem are anthropogenic influences on adaptive potential, including the prevention of gene flow through habitat fragmentation and the erosion of genetic diversity in small, bottlenecked populations. Facilitated adaptation, or assisted evolution, offers a way to augment adaptive genetic variation via artificial selection, induced hybridization, or genetic engineering. One key source of genetic variation, particularly for climatic adaptation, are the core metabolic genes encoded by the mitochondrial genome. These genes influence environmental tolerance to heat, drought, and hypoxia, but must interact intimately and co-evolve with a suite of important nuclear genes. These coadapted mitonuclear genes form some of the important reproductive barriers between species. Mitochondrial genomes can and do introgress between species in an adaptive manner, and they may co-introgress with nuclear genes important for maintaining mitonuclear compatibility. Managers should consider the relevance of mitonuclear genetic variability in conservation decision-making, including as a tool for facilitating adaptation. I propose a novel technique dubbed Conservation Mitonuclear Replacement (CmNR), which entails replacing the core metabolic machinery of a threatened species-the mitochondrial genome and key nuclear loci-with those from a closely related species or a divergent population, which may be better-adapted to climatic changes or carry a lower genetic load. The most feasible route to CmNR is to combine CRISPR-based nuclear genetic editing with mitochondrial replacement and assisted reproductive technologies. This method preserves much of an organism's phenotype and could allow populations to persist in the wild when no other suitable conservation options exist. The technique could be particularly important on mountaintops, where rising temperatures threaten an alarming number of species with almost certain extinction in the next century.

A kinetic dichotomy between mitochondrial and nuclear gene expression processes.

Oxidative phosphorylation (OXPHOS) complexes, encoded by both mitochondrial and nuclear DNA, are essential producers of cellular ATP, but how nuclear and mitochondrial gene expression steps are coordinated to achieve balanced OXPHOS subunit biogenesis remains unresolved. Here, we present a parallel quantitative analysis of the human nuclear and mitochondrial messenger RNA (mt-mRNA) life cycles, including transcript production, processing, ribosome association, and degradation. The kinetic rates of nearly every stage of gene expression differed starkly across compartments. Compared with nuclear mRNAs, mt-mRNAs were produced 1,100-fold more, degraded 7-fold faster, and accumulated to 160-fold higher levels. Quantitative modeling and depletion of mitochondrial factors LRPPRC and FASTKD5 identified critical points of mitochondrial regulatory control, revealing that the mitonuclear expression disparities intrinsically arise from the highly polycistronic nature of human mitochondrial pre-mRNA. We propose that resolving these differences requires a 100-fold slower mitochondrial translation rate, illuminating the mitoribosome as a nexus of mitonuclear co-regulation.