Mitochondrial Subunit Research Articles

Proteomic profiling reveals dysregulated mitochondrial complex subunits responsible for myocardial toxicity induced by SiNPs.

The relationship between environmental exposure to silica nanoparticles (SiNPs) and adverse cardiac outcomes has received more attention. Our recent work has revealed a size-dependent impact of the intratracheal instilled SiNPs on cardiac health of ApoE-/- mice using nanoscale SiNPs-60 and submicro-sized SiNPs-300, but the underlying mechanism of action still remains unclear. Hence, we identified proteins and protein networks perturbed by SiNPs in myocardial tissues of ApoE-/- mice by using LC-MS/MS-based quantitative proteomics. A set of 435 differentially expressed proteins (DEPs) were screened in response to SiNPs, which mainly enriched in the mitochondria and functioned in cell metabolism, biosynthesis and signal transduction. KEGG analysis showed that DEPs were significantly associated with oxidative phosphorylation and cardiomyopathy. The protein-protein interaction (PPI) network revealed 9 DEPs (e.g., Ndufs1, Ndufv1, Cox4i1) as potential biomarkers of SiNPs-induced myocardial toxicity. Of note, all the 9 candidate proteins were subunits of mitochondria respiratory chain complex, and their expressions were dependent on particle size, which were remarkably down-regulated by SiNPs-60 but not by SiNPs-300. More importantly, the correlation analysis verified the 9 dysregulated mitochondria complex protein subunits strongly correlated to the biochemical and functional indexes of cardiac injury in response to SiNPs. In conclusion, our study firstly provided significant proteomic insights into the potential molecular mechanisms underlying SiNPs-elicited cardiotoxicity, with the dysregulated mitochondrial complex subunits as core regulatory molecules. Overall, our study would provide the scientific basis for the molecular actions and mechanisms of toxicity induced by SiNPs.

Constitutive Expression of Hif2α Confers Acute O2 Sensitivity to Carotid Body Glomus Cells.

Acute oxygen (O2) sensing and adaptation to hypoxia are essential for physiological homeostasis. The prototypical acute O2 sensing organ is the carotid body, which contains chemosensory glomus cells expressing O2-sensitive K+ channels. Inhibition of these channels during hypoxia leads to cell depolarization, transmitter release, and activation of afferent sensory fibers terminating in the brain stem respiratory and autonomic centers. Focusing on recent data, here we discuss the special sensitivity of glomus cell mitochondria to changes in O2 tension due to Hif2α-dependent expression of several atypical mitochondrial electron transport chain subunits and enzymes. These are responsible for an accelerated oxidative metabolism and the strict dependence of mitochondrial complex IV activity on O2 availability. We report that ablation of Epas1 (the gene coding Hif2α) causes a selective downregulation of the atypical mitochondrial genes and a strong inhibition of glomus cell acute responsiveness to hypoxia. Our observations indicate that Hif2α expression is required for the characteristic metabolic profile of glomus cells and provide a mechanistic explanation for the acute O2 regulation of breathing.

Association of IMMP2L deletion with neurodevelopmental disorders: new case report and review of the literature.

The inner mitochondrial membrane peptidase subunit 2-like protein, the IMMP2L gene in 7q31.1, have been associated with different neurodevelopmental disorders, including autism spectrum disorders, attention deficit/hyperactivity disorder and Gilles de la Tourette's syndrome (GTS). Since the use of comparative genomic hybridization as essential tool in the diagnostic workup of neurodevelopmental disorders, recurrent microdeletions CNV's were identified in IMMP2L gene. We report here a 3 years old girl presenting since early life with complex motor tics, developmental delay, and other various cognitive/behavioral disturbances. Array CGH analysis showed a 331 Kb de novo pathogenic heterozygous deletion at 7q31.1 into the IMMP2L gene, involving exons 1 to 3. We discuss the functions of IMMP2L gene suggesting that his disruption may act as high-risk factor for neurodevelopmental disorders and movement disorders.

Latitudinal shift of the associated hosts inSagamiscintilla thalassemicola(Galeommatoidea: Galeommatidae), a rare ectosymbiotic bivalve that lives on the proboscis of echiuran worms

AbstractSagamiscintilla thalassemicola(Bivalvia: Galeommatoidea: Galeommatidae) is a rare ectocommensal bivalve that lives on the proboscis of echiuran worms,Anelassorhynchusspp. (Annelida: Thalassematidae: Thalassematinae: Thalassematini), and has been known only from the temperate zones of Japan. In this study, we foundS. thalassemicolaon the proboscis of the large echiuranOchetostomasp. (Thalassematidae: Thalassematinae: Thalassematini) on intertidal flats of three islands of the Ryukyu Archipelago, southern Japan. These are the first records ofS. thalassemicolaon non-Anelassorhynchushosts and also from the subtropical regions. Additionally, we also collectedS. thalassemicolafrom an intertidal flat of Kushimoto, Wakayama, Kii Peninsula, Japan, which is an update of the easternmost record of this species. The genetic differences in the mitochondrial cytochromecoxidase subunit I and nuclear internal transcribed spacer 2 genes amongS. thalassemicola, including those withOchetostomasp. from the subtropical region and withAnelassorhynchusspp. from the temperate region, can be considered within the intraspecific variation. These suggest thatS. thalassemicolauses different echiuran hosts in the temperate and subtropical regions, respectively.

PGC-1α/NRF1-dependent cardiac mitochondrial biogenesis: A druggable pathway of calycosin against triptolide cardiotoxicity.

Mitochondrion-related cardiotoxicity due to cardiotoxin stimuli is closely linked to abnormal activities of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), followed by co-inactivation of nuclear respiratory factor-1(NRF1). Pharmacological interventions targeting mitochondria may be effective for developing agents against cardiotoxicity. Herein, in triptolide-treated H9C2 cardiomyocytes, we observed defective mitochondrial biogenesis and respiration, characterized by depletion of mitochondrial mass and mitochondrial DNA copy number, downregulation of mitochondrial respiratory chain complexes subunits, and disorders of mitochondrial membrane potential and mitochondrial oxidative phosphorylation. Dysregulation of mitochondria led to cardiac pathological features, such as myocardial fiber fracture, intercellular space enlargement, and elevation of serum aspartate aminotransferase, creatine kinase isoenzyme, lactate dehydrogenase, and cardiac troponin I. However, following calycosin treatment, an active compound from Astragali Radix, the mitochondrion-related disorders at both cell and tissue levels were significantly ameliorated, which was facilitated by the activation of PGC-1α via deacetylation, followed by NRF1 co-activation. Calycosin-enhanced PGC-1α deacetylation is impelled by increasing sirtuin-1 expression and NAD+/NADH ratio. PGC-1α/NRF1 signaling in calycosin-mediated mitochondrial biogenesis protection was further confirmed by NRF1 knockdown and PGC-1α inhibition with SR18292. We conclude that calycosin ameliorated triptolide-induced cardiotoxicity by protecting PGC-1α/NRF1-dependent cardiac mitochondrial biogenesis and respiration, which is the druggable pathway for cardiotoxicity mitigation.

Molecular evidence for the first records and range extension of the great seahorse (Hippocampus kelloggi, Jordan & Snyder, 1901) in Quelimane, central coast of Mozambique

Abstract The family Syngnathidae contains 52 seahorse species, which inhabit a range of habitats including coral reefs, seagrass beds and coastal estuaries. The seahorse Hippocampus kelloggi is among the most widely distributed species, occurring from Indo-West Pacific to East Africa. This species was included in the IUCN Red List in 2017 and is classified as vulnerable according to A2cd criteria. In this study, three specimens collected from the central coast of Mozambique were investigated and based on morphology and mitochondrial subunit of cytochrome oxidase I (COI) were identified as H. kelloggi. These results confirmed for the first time the extensive range of occurrence of H. kelloggi on the central coast of Mozambique.

Proteogenomic analysis of acute myeloid leukemia associates relapsed disease with reprogrammed energy metabolism both in adults and children

Despite improvement of current treatment strategies and novel targeted drugs, relapse and treatment resistance largely determine the outcome for acute myeloid leukemia (AML) patients. To identify the underlying molecular characteristics, numerous studies have been aimed to decipher the genomic- and transcriptomic landscape of AML. Nevertheless, further molecular changes allowing malignant cells to escape treatment remain to be elucidated. Mass spectrometry is a powerful tool enabling detailed insights into proteomic changes that could explain AML relapse and resistance. Here, we investigated AML samples from 47 adult and 22 pediatric patients at serial time-points during disease progression using mass spectrometry-based in-depth proteomics. We show that the proteomic profile at relapse is enriched for mitochondrial ribosomal proteins and subunits of the respiratory chain complex, indicative of reprogrammed energy metabolism from diagnosis to relapse. Further, higher levels of granzymes and lower levels of the anti-inflammatory protein CR1/CD35 suggest an inflammatory signature promoting disease progression. Finally, through a proteogenomic approach, we detected novel peptides, which present a promising repertoire in the search for biomarkers and tumor-specific druggable targets. Altogether, this study highlights the importance of proteomic studies in holistic approaches to improve treatment and survival of AML patients.

TMIC-76. HUMANIN RELEASE FROM TUMOR ASSOCIATED MYELOID CELLS PROMOTES GLIOMA CHEMORESISTANCE

Abstract Transcriptomic screens of brain tumor (glioblastoma; GBM) parenchymal cells indicated tumor supporting traits of the GBM microenvironment, but largely excluded mitochondrially enriched gene-sets. Here, we show that a mitochondrial transcript of GBM parenchymal cells contributes to therapy resistance. We inspected the non-coding transcriptome of human GBM associated myeloid cells (GAM) and observed an upregulation of the mitochondrial ribosomal subunit MT-RNR2, which contains an open reading frame for the signaling peptide humanin. Immunohistology disclosed that humanin was preponderant in GAM. In vitro assays with a range of human stem-like GBM cells (GSCs) revealed that nanomolar concentrations of humanin can drive tumor cell expansion and chemoresistance to temozolomide. A series of genetic, pharmacological and Western blotting experiments showed that extracellular humanin increased GSC viability via stimulation of the GP130/IL6ST receptor and MAPK (Erk) activation. Humanin responsiveness was subject to inter-individual heterogeneity and predominated in GSC with high expression levels of the IL6ST subunit. Mechanistically, humanin promoted the ATR-dependent DNA-repair machinery in GSCs via induction of the DNA-clamp component HUS1. A slice culture model containing human microglia and GSCs confirmed these observations. Humanin is absent from the mouse brain. Exogenous delivery of humanin into orthotopic GBM mouse models or over-expression specifically of a secreted humanin variant recapitulated the in vitro findings. Blockade of the trimeric interleukin receptor with the brain permeant, FDA-approved drug bazedoxifene blocked humanin-mediated chemoresistance in vitro and in vivo. Overall, we identified a clinically applicable compound together with a predictive marker to prevent chemoresistance in a human-specific GBM model.

Abstract 11961: Ductus Arteriosus Oxygen Response is Mediated by Mitochondrial Subunit NDUFS2

Introduction: The ductus arteriosus (DA) is a fetal vessel connecting the pulmonary artery (PA) and aorta, diverting oxygenated blood away from the developing lungs to the systemic circulation. The DA rapidly constricts in response to the increase in arterial oxygen (O 2 ) following the first breath. Failure of the DA to close in response to O 2 results in persistent ductus arteriosus, one of the most common complications of preterm birth. Mitochondria are known to play an important role in the O 2 response of DA smooth muscle cells (DASMC), however the mechanism is not fully understood. A subunit of mitochondrial Complex I, NDUFS2 (NADH:ubiquinone oxidoreductase core subunit 2) mediates the O 2 response of other specialized O 2 sensing tissues (PA and carotid body); we assess whether NDUFS2 also plays a role in DA O 2 sensing. Methods: DASMC were isolated from male term (29 days gestation) fetal New Zealand white rabbits. Cell lines were purified via fluorescence activated cell sorting, excluding CD90 + and CD31 + cells (fibroblasts and endothelial cells, respectively). Smooth muscle cell purity was confirmed using flow cytometry for α-smooth muscle actin (α-SMA). Primary cultures were 97.65% ± 0.65% CD90 - CD31 - , and were 100% α-SMA + post-sorting. We measured the O 2 responsiveness of DASMC using confocal microscopy, measuring changes in intracellular calcium with Cal-520AM. Cells were cultured in hypoxia (2.5% O 2 , pO 2 = 41 mmHg), with O 2 -induced increase in calcium relative to hypoxic baseline serving as a surrogate for constriction. DASMC were treated for 48 hours with 30 pmol siRNA and 90 pmol Lipofectamine® RNAiMAX to knockdown gene expression of NDUFS2 or a negative control. Knockdown was confirmed using qPCR. Results & Conclusions: There was a 14.7% (±2.6%, n=33, p<0.0001) increase in intracellular calcium relative to hypoxic baseline in siNC-treated cells. O 2 response was obliterated when treated with siNDUFS2 (0.7% ± 2.1%, n=29, p=0.798), with a 90.9% ± 1.89% knockdown of NDUFS2 mRNA expression. These data suggest a critical role for the mitochondrial electron transport chain, specifically NDUFS2, in DA oxygen responsiveness. While further functional studies will be required, our findings suggest a novel potential therapeutic target to modulate DA patency.

Morphological and molecular phylogenetic data reveal another new species of bent-toed gecko (Cyrtodactylus Gray: Squamata: Gekkonidae) from Mizoram, India

ABSTRACT A new species of Cyrtodactylus is described herein on the basis of morphological and phylogenetic evidence inferred from the mitochondrial nicotinamide adenine dinucleotide hydride dehydrogenase subunit 2 gene from Mizoram, Northeast India. The new species is distinguished from its congeners by an adult snout-vent length of 62.6–68.6 mm; 10–11 supralabials; 9–11 infralabials; dorsal tubercles rounded, conical to weakly keeled and in 19–20 longitudinal rows; 32–36 paravertebral tubercles between the level of axilla and groin; 32–39 mid-ventral scale rows across the ventral region; 6 precloacal pores in males and 0–6 precloacal pits in females; 14–18 subdigital lamellae under toe IV; no single row of transversely enlarged subcaudal scales; indistinct pattern of alternating dark brown blotches on the dorsum of the body. Morphologically and genetically, the new species is recovered as the sister species to C. aaronbaueri, but is genetically distinct by an uncorrected p-distance of 0.099–0.1, and morphologically in the number of precloacal pores, mid-ventral scale rows, paravertebral tubercles on the trunk, dorsal tubercle rows, dorsal spot, and subdigital lamellae on pes. http://www.zoobank.org/urn:lsid:zoobank.org:pub:8E9144FA-EFAF-4C7D-B64F-667706643EC5

Mitochondrial genomic analyses provide new insights into the “missing” atp8 and adaptive evolution of Mytilidae

BackgroundMytilidae, also known as marine mussels, are widely distributed in the oceans worldwide. Members of Mytilidae show a tremendous range of ecological adaptions, from the species distributed in freshwater to those that inhabit in deep-sea. Mitochondria play an important role in energy metabolism, which might contribute to the adaptation of Mytilidae to different environments. In addition, some bivalve species are thought to lack the mitochondrial protein-coding gene ATP synthase F0 subunit 8. Increasing studies indicated that the absence of atp8 may be caused by annotation difficulties for atp8 gene is characterized by highly divergent, variable length.ResultsIn this study, the complete mitochondrial genomes of three marine mussels (Xenostrobus securis, Bathymodiolus puteoserpentis, Gigantidas vrijenhoeki) were newly assembled, with the lengths of 14,972 bp, 20,482, and 17,786 bp, respectively. We annotated atp8 in the sequences that we assembled and the sequences lacking atp8. The newly annotated atp8 sequences all have one predicted transmembrane domain, a similar hydropathy profile, as well as the C-terminal region with positively charged amino acids. Furthermore, we reconstructed the phylogenetic trees and performed positive selection analysis. The results showed that the deep-sea bathymodiolines experienced more relaxed evolutionary constraints. And signatures of positive selection were detected in nad4 of Limnoperna fortunei, which may contribute to the survival and/or thriving of this species in freshwater.ConclusionsOur analysis supported that atp8 may not be missing in the Mytilidae. And our results provided evidence that the mitochondrial genes may contribute to the adaptation of Mytilidae to different environments.

The Role of Mitochondrial Subunits in the Opposing Oxygen Responses of the Ductus Arteriosus and Pulmonary Arteries

The Role of Mitochondrial Subunits in the Opposing Oxygen Responses of the Ductus Arteriosus and Pulmonary Arteries

Phylogeographic patterns in attached and free-living marine macroalga Fucus vesiculosus (Fucaceae, Phaeophyceae) in the Baltic Sea

Abstract Sequencing of a mitochondrial intergenic spacer and 23S subunit was used to investigate the phylogeographic patterns in Fucus vesiculosus. Samples originated from 21 sites spanning six subbasins of the Baltic Sea. We identify a putative ancestral mitochondrial haplotype that entered the Baltic Sea from the Atlantic, colonising extensively throughout the species’ distribution. The dominance of this haplotype is seen in the low overall haplotype diversity (H d = 0.29). Moreover, there is indication of few spatially aggregated patterns in the deeper demographic time scales (F ct = 0.040; F st = 0.049). Tajima’s D (−0.685, p-value 0.297) and Fu’s F S (0.267, p-value 0.591) showed no significant signals of extreme demographic changes. The Baltic Sea free-living Fucus is confirmed as F. vesiculosus or a closely related species. Haplotype diversities are comparable between forms (attached H d = 0.306; free-living H d = 0.268). The relatively short temporal scale for colonisation alongside low variance in the Fucus mitochondrial genome results in a rather panmictic structure across the Baltic Sea. Our data suggest that the mitochondrial intergenic spacer and 23S poorly describe the evolutionary dynamics of Fucus spp. in such a young, postglacial environment, yet this concatenated-barcode advances our understanding of the colonisation dynamics of F. vesiculosus over deeper demographic timescales.

Zhen Wu decoction represses renal fibrosis by invigorating tubular NRF2 and TFAM to fuel mitochondrial bioenergetics

BackgroundZhen Wu Decoction (ZWD) is a prescription from the classical text “Treatise on Exogenous Febrile Disease” and has been extensively used to control kidney diseases since the time of the Eastern Han Dynasty. HypothesisWe hypothesized that ZWD limits tubular fibrogenesis by reinvigorating tubular bio-energetic capacity. Study Design / MethodsA mouse model of chronic kidney disease (CKD) was established using unilateral ureteral obstruction (UUO). Three concentrations of ZWD, namely 25.2 g/kg (high dosage), 12.6 g/kg (middle dosage), and 6.3 g/kg (low dosage), were included to study the dose-effect relationship. Real-time qPCR was used to observe gene transcription in blood samples from patients with CKD. Different siRNAs were designed to study the role of mitochondrial transcription factor A (TFAM) and nuclear factor (erythroid-derived 2)-related factor 2 (NRF2) in transforming growth factor (TGF)-β1 induced fibrogenesis and mitochondrial damage. ResultsWe showed that ZWD efficiently attenuates renal function impairment and reduces renal interstitial fibrosis. TFAM and NRF2 were repressed, and the stimulator of interferon genes (STING) was activated in CKD patient blood sample. We further confirmed that ZWD activated TFAM depended on NRF2 as an important negative regulator of STING in mouse kidneys. Treatment with ZWD significantly reduced oxidative stress and inflammation by regulating the levels of oxidative phosphorylation (OXPHOS) and pro-inflammatory factors, such as interleukin-6, interleukin-1β, tumor necrosis factor receptor 1, and mitochondrial respiratory chain subunits. NRF2 inhibitors can weaken the ability of ZWD to increase TFAM expression and heal injured mitochondria, playing a similar role to that of STING inhibitors. Our study showed that ZWD elevates the expression of TFAM and mitochondrial respiratory chain subunits by promoting NRF2 activation, after suppressing mitochondrial membrane damage and cristae breakdown and restricting mitochondrial DNA (mtDNA) leakage into the cytoplasm to reduce STING activation. ConclusionZWD maintains mitochondrial integrity and improves OXPHOS which represents an innovative insight into “strengthening Yang-Qi” theory. ZWD limits tubular fibrogenesis by reinvigorating tubular bioenergetic capacity.

A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.

SummaryMitochondrial diseases are a heterogeneous group of genetic disorders caused by pathogenic variants in genes encoding gene products that regulate mitochondrial function. These genes are located either in the mitochondrial or in the nuclear genome. The TOMM7 gene encodes a regulatory subunit of the translocase of outer mitochondrial membrane (TOM) complex that plays an essential role in translocation of nuclear-encoded mitochondrial proteins into mitochondria. We report an individual with a homozygous variant in TOMM7 (c.73T>C, p.Trp25Arg) that presented with a syndromic short stature, skeletal abnormalities, muscle hypotonia, microvesicular liver steatosis, and developmental delay. Analysis of mouse models strongly suggested that the identified variant is hypomorphic because mice homozygous for this variant showed a milder phenotype than those with homozygous Tomm7 deletion. These Tomm7 mutant mice show pathological changes consistent with mitochondrial dysfunction, including growth defects, severe lipoatrophy, and lipid accumulation in the liver. These mice die prematurely following a rapidly progressive weight loss during the last week of their lives. Tomm7 deficiency causes a unique alteration in mitochondrial function; despite the bioenergetic deficiency, mutant cells show increased oxygen consumption with normal responses to electron transport chain (ETC) inhibitors, suggesting that Tomm7 deficiency leads to an uncoupling between oxidation and ATP synthesis without impairing the function of the tricarboxylic cycle metabolism or ETC. This study presents evidence that a hypomorphic variant in one of the genes encoding a subunit of the TOM complex causes mitochondrial disease.

Effects of Endurance Training on Metabolic Enzyme Activity and Transporter Proteins in Skeletal Muscle of Ovariectomized Mice.

Estrogen deficiency or insufficiency can occur under several conditions, leading to negative health outcomes. To establish an effective countermeasure against estrogen loss, we investigated the effects of endurance training on ovariectomy (OVX)-induced metabolic disturbances. Female Institute of Cancer Research mice underwent OVX or sham operations. On day 7 of recovery, the mice were randomized to remain either sedentary or undergo 5 wk of treadmill running (15-20 m·min -1 , 60 min, 5 d·wk -1 ). During week 5 of the training, all animals performed a treadmill running test (15 m·min -1 , 60 min). After the experimental period, OVX resulted in greater gains in body mass, fat mass, and triglyceride content in the gastrocnemius muscle. OVX enhanced phosphofructokinase activity in the plantaris muscle and decreased lactate dehydrogenase activity in the plantaris and soleus muscles. OVX decreased the protein content of NDUFB8, a mitochondrial respiratory chain subunit, but did not decrease other mitochondrial proteins or enzyme activities. Endurance training significantly enhanced mitochondrial enzyme activity and protein content in the skeletal muscles. Although OVX increased the respiratory exchange ratio during the treadmill running test, and postexercise blood lactate levels, endurance training normalized these parameters. The present findings suggest that endurance training is a viable strategy to counteract the negative metabolic consequences in hypoestrogenism.

Deeper diversity exploration: New Typhlotanaidae (Crustacea: Tanaidacea) from the Kuril-Kamchatka Trench area

Typhlotanaidae Sieg, 1984, is one of the most diverse Tanaidacea families from deep-sea waters. Its diversity is underestimated, and evolutionary relationships within the family remain mostly unknown. Deep-sea typhlotanaids collected from 23 sites across the Kuril-Kamchatka Trench and nearby waters were studied using an integrative taxonomy approach, combining morphological and genetic data (i.e., the mitochondrial subunit I of the cytochrome oxidase (COI) and the 18S rDNA nuclear gene). One new species ofTyphlamiaand two new species belonging to two new genera are described, significantly increasing the known diversity of typhlotanaids from the NW Pacific. The molecular phylogeny obtained, despite being preliminary results, was congruent with morphological data and supports the monophyly of different groups such as the ‘short-bodied’ forms (represented byTy. cornutusandTy. eximius) or the ‘collar’ forms (e.g.,Ty. variabilisandTorquella). Molecular data confirm the non-monophyly ofTyphlotanaisspecies. Finally, the new typhlotanaid taxa seem to have distinct bathymetric distribution and ecological requirements, but further data on environmental factors and species abundances are still needed.

Role of mitochondrial translation in remodeling of energy metabolism in ER/PR(+) breast cancer.

Remodeling of mitochondrial energy metabolism is essential for the survival of tumor cells in limited nutrient availability and hypoxic conditions. Defects in oxidative phosphorylation (OXPHOS) and mitochondrial biogenesis also cause a switch in energy metabolism from oxidative to aerobic glycolysis contributing to the tumor heterogeneity in cancer. Specifically, the aberrant expressions of mitochondrial translation components such as ribosomal proteins (MRPs) and translation factors have been increasingly associated with many different cancers including breast cancer. The mitochondrial translation is responsible for the synthesis 13 of mitochondrial-encoded OXPHOS subunits of complexes. In this study, we investigated the contribution of mitochondrial translation in the remodeling of oxidative energy metabolism through altered expression of OXPHOS subunits in 26 ER/PR(+) breast tumors. We observed a significant correlation between the changes in the expression of mitochondrial translation-related proteins and OXPHOS subunits in the majority of the ER/PR(+) breast tumors and breast cancer cell lines. The reduced expression of OXPHOS and mitochondrial translation components also correlated well with the changes in epithelial-mesenchymal transition (EMT) markers, E-cadherin (CHD1), and vimentin (VIM) in the ER/PR(+) tumor biopsies. Data mining analysis of the Clinical Proteomic Tumor Analysis Consortium (CPTAC) breast cancer proteome further supported the correlation between the reduced OXPHOS subunit expression and increased EMT and metastatic marker expression in the majority of the ER/PR(+) tumors. Therefore, understanding the role of MRPs in the remodeling of energy metabolism will be essential in the characterization of heterogeneity at the molecular level and serve as diagnostic and prognostic markers in breast cancer.

Genetic variation of sequences of partial mitochondrial nicotinamide adenine dinucleotide dehydrogenase subunit 1 (pnad1) and pnad5 genes of Toxascaris leonina isolates from foxes and dogs in Jiuquan City of Gansu Province

To investigate the genetic variations of Toxascaris leonina isolates from different hosts in Jiuquan City, Gansu Province. The mitochondrial sequences of partial mitochondrial nicotinamide adenine dinucleotide dehydrogenase subunit 1 (pnad1) and pnad5 of eleven T. leonina isolates from domestic dogs, foxes and pet dogs in Jiuquan City, Gansu Province, were amplified using PCR, and the amplification product was sequenced. The genetic variations of pnad1 and pnad5 genes in T. leonina isolates were analyzed. The sequences of T. leonina pnad1 and pnad5 genes measured 530 bp and 550 bp in size, respectively. The nucleotide sequence homology was 99.4% to 100.0% for T. leonina pnad1 gene and 99.5% to 99.8% for T. leonina pnad5 gene, and the sequences of T. leonina pnad1 and pnad5 genes shared 99.2% to 99.9% and 99.1% to 99.9% with corresponding sequences of known T. leonina isolates. In addition, there were 19 and 24 polymorphic sites detected in the sequences of T. leonina pnad1 and pnad5 genes, with 10 and 9 haplotypes, haplotype diversity of 0.982 and 0.964 and nucleotide diversity of 0.039 4 and 0.034 2, respectively. Phylogenetic analysis based on pnad1 and pnad5 gene sequences showed that the eleven T. leonina isolates and known T. leonina isolates were clustered into the same branch with a random distribution, which were close to the branch where Toxocara canis was clustered, and far from the branch where other Ascaris species were clustered. There is a minor genetic variation in pnad1 and pnad5 genes of T. leonina isolates from different hosts in Jiuquan City, Gansu Province, and the pnad1 gene is more suitable as a molecular marker than pnad5 gene for analysis of genetic variations in T. leonina.

Balanced mitochondrial and cytosolic translatomes underlie the biogenesis of human respiratory complexes

BackgroundOxidative phosphorylation (OXPHOS) complexes consist of nuclear and mitochondrial DNA-encoded subunits. Their biogenesis requires cross-compartment gene regulation to mitigate the accumulation of disproportionate subunits. To determine how human cells coordinate mitochondrial and nuclear gene expression processes, we tailored ribosome profiling for the unique features of the human mitoribosome.ResultsWe resolve features of mitochondrial translation initiation and identify a small ORF in the 3′ UTR of MT-ND5. Analysis of ribosome footprints in five cell types reveals that average mitochondrial synthesis levels correspond precisely to cytosolic levels across OXPHOS complexes, and these average rates reflect the relative abundances of the complexes. Balanced mitochondrial and cytosolic synthesis does not rely on rapid feedback between the two translation systems, and imbalance caused by mitochondrial translation deficiency is associated with the induction of proteotoxicity pathways.ConclusionsBased on our findings, we propose that human OXPHOS complexes are synthesized proportionally to each other, with mitonuclear balance relying on the regulation of OXPHOS subunit translation across cellular compartments, which may represent a proteostasis vulnerability.