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PubMed2025

COXFA4L3 enhances mitochondrial complex IV function to boost ATP synthesis and drive sperm motility.

COXFA4L3 is a testis-specific cytochrome c oxidase subunit that enhances mitochondrial complex IV activity during spermatogenesis. From the analysis of Coxfa4l3 knockout mice, the isoform switch from COXFA4 to COXFA4L3 may increase the potential COX activity, although this activity does not appear in the testis. This latent enhancement becomes evident in sperm, where COXFA4L3 promotes higher respiratory capacity, increasing sperm motility and ATP production. These findings indicate that COXFA4L3 is a key regulator of mitochondrial energy metabolism and may provide insights into the mechanisms underlying male infertility.

Electron Transport Complex IV↗

PubMed2025

Biallelic FOXRED1 mutations cause infantile mitochondrial encephalopathy with complex I disassembly and basal ganglia degeneration.

Developmental and epileptic encephalopathy (DEE) is a severe neurological disorder. Biallelic mutations in the nuclear-encoded mitochondrial chaperone gene FOXRED1, a specific assembly factor for complex I, cause mitochondrial dysfunction; however, their role in DEE pathogenesis remains unexplored. Clinical data and peripheral blood mononuclear cells (PBMCs) were obtained from two patients with compound heterozygous FOXRED1 mutations (c.850T>C (p.C284R)/c.1054C>T (p.R352W) and c.1054C>T (p.R352W)/c.3dup (p.I2Dfs*35) and age-matched controls. Mitochondrial phenotyping, included complex I activity, mitochondrial respiration stress test, membrane potential, intracellular ROS, and NAD+/NADH ratio, were performed. Both patients exhibited early-onset refractory seizures, basal ganglia lesions, hyperlacticemia, and developmental regression. FOXRED1 mutations resulted in 50% reduction in complex I activity, dissasembly of complex I, mitochondrial depolarization, oxidative stress, and NAD+/NADH imbalance. Niacin restored the NAD+/NADH ratio in vitro, while clinical supplementation reduced blood lactate levels, suggesting it may be a potential therapeutic option.

Humans↗

PubMed2026

Natural variation in Miniature5 determines mitochondrial nad1 splicing and seed development in maize.

Seed size is a key determinant of cereal grain yield, but natural variations in defective-kernel genes have rarely been applied in maize breeding. Here, we report the positional cloning of maize Miniature5 (Mn5), which encodes a mitochondrial-targeted P-class pentatricopeptide repeat (PPR) protein. Further analysis shows that a missense mutation of Mn5, Mn5Val109, presents in maize populations and correlates with reduced seed size. The Mn5Val109 variant exhibits compromised function in the miniature5 (mn5-ref) mutant, failing to trans-splice mitochondrial nad1 intron1, drastically reducing the abundance and activity of respiratory complex I, accompanied by disorganized mitochondrial cristae. Mn5 directly binds to domain IV of the pre-nad1.1 transcript. Notably, this binding site is located downstream of the previously presumed 3'-terminus bound by MITOCHONDRIA STABILITY/PROCESSING PPR FACTOR1 (MSP1), thus redefining the 3'-end of the nad1.1 pre-RNA. Furthermore, Mn5 physically interacts with the maturases ZmnMAT1 and ZmnMAT3, as well as the PPR proteins PPR-SMR1 and SPR2, which are broadly involved in organellar group II intron splicing. Together, our results suggest that Mn5 recruits maturases and PPR proteins to form spliceosomal complexes responsible for the trans-splicing of nad1 intron1. Importantly, natural variations in Mn5 confer differences in seed size control, offering potential for breeding high-yield maize varieties.

Zea mays↗

PubMed2026

Emergence and phylogeography of the dengue vector Aedes aegypti in Southeastern Iran.

BACKGROUND: Aedes (Stegomyia) aegypti (Linnaeus) is the primary vector of dengue, chikungunya, Zika, and yellow fever viruses. Its recent detection in southeastern Iran raises public health concerns about arbovirus spread to new regions. This study provides the first genetic and phylogeographic analysis of Ae. aegypti populations from Sistan and Baluchistan Province (SBP), Iran, to infer their origin and invasion pathways. METHODS: Mitochondrial COI and ND4 genes were analysed in newly collected Ae. aegypti specimens from border areas, ports, and urban centres of SBP. Haplotype network analyses were constructed using the TCS method in PopART, and phylogenetic analyses were conducted using global reference sequences. RESULTS: Iranian specimens comprised 7 COI haplotypes (n = 18) and 10 ND4 haplotypes (n = 17). COI phylogeny placed Iranian specimens into two main clades, while ND4 analysis distributed them across several derived clades, mostly clustering with lineages from Latin America (Brazil, Mexico) or Africa. One Iranian specimen showed a close relationship with a Saudi Arabian sequence (bootstrap: 98%) near the basal region. Combined COI + ND4 analysis revealed a monophyletic clade of Iranian specimens with a Sri Lankan specimen, distinct from other global lineages. The global COI network (n = 47) showed a star-like topology with a dominant haplotype 1 shared among 10 Iranian specimens. The ND4 network (n = 31) revealed a complex topology with 18 haplotypes, where a Saudi Arabian and one Iranian specimen (~30 mutational steps) possibly represented the peripheral root. CONCLUSIONS: Detection of diverse Ae. aegypti clades confirm establishment of this vector in southeastern Iran. Results support multiple introductions and genetic connectivity with Latin America, Africa, and South Asia, pointing to an emerging invasion corridor. Continued genomic surveillance and integrated vector monitoring are urgently needed to guide prevention strategies.

Animals↗

PubMed2025

Complex IV deficiency due to COX4I1 deep intronic and de novo variants results in progressive motor impairment and Leigh syndrome.

COX4I1 gene encodes cytochrome c oxidase subunit 4 isoform 1, involved in the early assembly stages of mitochondrial respiratory chain complex IV. To date, COX4I1 pathogenic variants have been reported in only a few cases, each exhibiting heterogeneous clinical phenotypes and limited functional data. Here, we describe the fourth reported case of COX4I1 deficiency associated with human disease, expanding the phenotypic and genetic spectrum of this rare mitochondrial disorder and providing novel clinical, molecular, and functional data. The herein reported individual presented with progressive deterioration of motor skills, intellectual disability and brain imaging abnormalities compatible with Leigh syndrome. Genetic studies combining short and long read next generation sequencing uncovered a peculiar genetic combination in this patient, harboring a de novo COX4I1 nonsense substitution in trans with an inherited deep intronic variant (c.[64C>T];[73+1511A>G]; p.[Arg22Ter];[Glu25ValfsTer9]). Functional studies performed in patient's tissues and transiently transfected cell lines demonstrated that the identified variants mainly exert their pathogenic effect by targeting COX4I1 protein levels, thereby impairing the proper assembly and activity of complex IV.Additionally, proteomic data in patient's fibroblasts suggested an underlying pathomechanism that involves not only the regulation of complex IV function but also the levels of mitoribosomal proteins. In summary, our findings shed light to clarify some of the main clinical features associated with COX4I1 deficiency and the molecular mechanisms involved in the pathogenesis of this disorder.

Humans↗

PubMed2026

COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy.

Primary mitochondrial diseases (PMDs) affect approximately 1 in 4300 individuals and cause early-onset neuromuscular and multisystem dysfunction with reduced lifespan. They result from pathogenic variants in mitochondrial or nuclear DNA that impair oxidative phosphorylation. Cytochrome c oxidase (COX; complex IV) deficiency is a well-established cause of PMD, leading to a broad spectrum of phenotypes. COXFA4 (cytochrome c oxidase subunit FA4), formerly NDUFA4, is a nuclear-encoded COX subunit, but its role in disease remains poorly defined. We report the largest genetically confirmed cohort of COXFA4-related PMD to date, comprising 13 individuals from 12 families with biallelic pathogenic COXFA4 variants. All present with Leigh-like encephalopathy and complete loss of COXFA4 protein; however, patient-derived fibroblasts retain residual COX activity, with upregulation of COXFA4L2 (cytochrome c oxidase subunit FA4-like 2), a poorly characterised paralog. Here, we show that COXFA4 is a late-stage COX assembly subunit and identify a paralog-mediated compensatory mechanism with translational potential.

Humans↗

PubMed2024

Oceanic islands act as drivers for the genetic diversity of marine species: Cardita calyculata (Linnaeus, 1758) in the NE Atlantic as a case-study.

Geographic distribution, as well as evolutionary and biogeographic processes and patterns of marine invertebrate benthic species are strongly shaped by dispersal ability during the life cycle. Remote oceanic islands lie at the brink of complex biotic and abiotic interactions which have significantly influenced the biodiversity patterns we see today. The interaction between geological environmental change and taxon-specific dispersal modes can influence species evolutionary patterns, eventually delimiting species-specific biogeographic regions. In this study, we compare the population genetic patterns of the marine bivalve Cardita calyculata in the northeast Atlantic, discussing the role of Macaronesian islands during past climatic cycles. The genetic structure and diversity patterns were outlined based on SSR-GBAS loci of 165 individuals and on the mitochondrial COI marker of 22 individuals from the Canary Islands, Madeira, Azores and the Mediterranean. The highly structured genetic pattern found among regions and within archipelagos suggests the central role of oceanic islands in promoting the divergence of the species in both the NE Atlantic and the Mediterranean. The high degree of divergence in the COI dataset (> 7%) suggests the existence of potential cryptic speciation that needs to be further explored with a more comprehensive sampling. Such patterns are only congruent with a scenario where C. calyculata populations were maintained during glacial/interglacial cycles, supporting the role of the studied archipelagos as drivers of diversity for marine biota. We stress the importance of developing studies for species with various life history and dispersal modes. In such a way, a more profound understanding of the biogeographic and evolutionary significance of oceanic islands can catalyse directed conservation efforts, especially in the context of the ongoing climate crisis.

Animals↗

PubMed2026

The pseudokinase domain PK1 of UNC-89/obscurin is required for mitochondrial morphology and function in C. elegans.

UNC-89 is a giant modular protein located at the sarcomeric M-line of C. elegans striated muscle and is required for sarcomere organization and function. UNC-89 contains two protein kinase domains, PK1 and PK2, separated by 850 residues, that includes a 645-residue long intrinsically disordered sequence that acts like an elastic spring. Bioinformatic analysis suggests that PK2 is an active kinase whereas PK1 is a pseudokinase. We recently reported that a genome-edited worm, unc-89(sf22), that expresses UNC-89 carrying a kinase-inactivating point mutation in PK2 has an unusual phenotype with normally organized sarcomeres and SR, normal muscle function and yet fragmented mitochondria, increased ATP levels, increased glycolysis and alterations in electron transport chain complexes and respiration. Here, we show that a genome-edited worm unc-89(sf23), that expresses UNC-89 with an in-frame deletion of the C-lobe of PK1 has approximately the same phenotype as the PK2 catalytically dead mutant. The fact that mutations in two different regions of UNC-89 result in a mitochondrial phenotype is further evidence of communication between the sarcomere and mitochondria. We further demonstrate that in vitro PK2 interacts with full length PK1 and the C-lobe of PK1. The protein kinase domains of giant sarcomeric proteins are autoinhibited by parts of their own sequence, and this is also likely for PK2, but the mechanism by which PK2 would be activated is unknown. Our data is compatible with a model in which PK1 interacts with PK2 and thereby stimulates PK2 kinase activity.

Animals↗

PubMed2026

Expression and mutation characteristics of mitochondrial genes in PBMCs of SLE patients: Implications for SLE pathogenesis.

This study aimed to investigate mitochondrial gene mutations and expression in peripheral blood mononuclear cells (PBMCs) of systemic lupus erythematosus (SLE) patients, focusing on MT-ND5, and assess expression changes under lipopolysaccharide (LPS), tumor necrosis factor-α (TNF-α), and dexamethasone stimulation. Peripheral blood was collected from female SLE patients. Mitochondrial DNA (mtDNA) from PBMCs was sequenced using the HiSeq PE150 platform. Quantitative reverse transcription PCR and western blotting were used to evaluate mRNA and protein expression of the most frequently mutated mitochondrial genes. Cultured PBMCs were treated with LPS, TNF-α, or dexamethasone to examine regulatory effects. A total of 589 mtDNA mutation sites were detected in SLE patients. Among 13 protein-coding genes, MT-ND5, MT-CYB, MT-CO1, MT-ND4, and MT-CO3 exhibited the highest mutation frequencies. Expression analysis revealed significantly reduced mRNA and protein levels of these genes in SLE PBMCs compared with controls, with further decreases after stimulation with LPS, TNF-α, or dexamethasone. SLE PBMCs display extensive mitochondrial mutations and downregulation of key genes, particularly MT-ND5. Inflammatory and therapeutic stimuli exacerbate this suppression, suggesting mitochondrial dysfunction contributes to SLE susceptibility and progression.

Humans↗

PubMed2026

Getting to the Core of the Matter-Assessing the Role of Replication in Metabarcoding-Based sedaDNA.

Replication is central to most experimental and sampling designs, increasing inferential power and capturing fine-scale data heterogeneity. However, its importance remains poorly evaluated in some ecological and evolutionary settings. This is the case of metabarcoding studies using DNA recovered from sedimentary archives, in which biological signals integrate ecological information through depositional and burial processes, yet are commonly inferred from a single sediment core per site. Here, we evaluated the effect of different types of replication using sedimentary DNA metabarcoding data from two genetic markers (mitochondrial COI and nuclear 18S) using a nested sampling design. The design included three intertidal sites, three spatially separated sediment cores per site (biological replicates), two sediment horizons per core, and eight PCR (technical) replicates per sediment sample. Variance partitioning showed that site identity and sediment age group together explained > 70% of the variation in beta diversity, indicating that among-site spatial and stratigraphic differences were the dominant drivers of community composition. PERMANOVA likewise identified non-significant effects of biological replication. Among PCR replicates from the same sediment sample, richness varied substantially, whereas Shannon diversity was more consistent. Despite this variability, differences in community composition among technical replicates remained smaller than those associated with biological replication or site identity, indicating a limited influence on broader ecological patterns. Community composition was highly similar among replicate cores within sites, consistent with stratigraphic coherence. These results indicate limited within-site heterogeneity and suggest that, under stratigraphically coherent conditions, increasing biological replication may provide little additional information, whereas enhancing technical replication and stratigraphic resolution can improve ecological inference from sedimentary DNA metabarcoding datasets.

DNA Barcoding, Taxonomic↗

PubMed2026

Genetic differentiation of the supralittoral gastropod Tectarius striatus (North Atlantic Archipelagos) and development of new microsatellite resources.

Microsatellite markers are invaluable tools for assessing genetic diversity and elucidating population structure across any species. This study reports the development and application of ten novel polymorphic microsatellite loci for Tectarius striatus, a littorinid species native to the shores of Macaronesia, a geographical region that includes the archipelagos of the Azores, Madeira, Selvagens, Canary Islands, and Cabo Verde. These markers together with a portion of the COI gene were used to genotype 65 individuals, using Illumina amplicon -sequencing across five geographically distinct populations. Our analysis shows moderate to high levels of allelic diversity across all populations. Furthermore, microsatellite markers supported genetic structure between a distant population of Cabo Verde Archipelago and the northern Macaronesian archipelagos. Conversely variation of the COI showed high levels of homogeneity across the sampled populations. While the presence of null alleles and moderate levels of missing data at several loci represent challenges to this study, the overall consistency of our results with earlier research underscores the reliability of microsatellite markers for population genetic inference in this marine gastropod. Nevertheless, our findings highlight the need for cautious interpretation of diversity estimates and population structure metrics, particularly when null alleles are frequent, and underscore the value of expanding the panel of available microsatellite markers for Tectarius striatus and related taxa to improve resolution and accuracy for future studies.

Animals↗

PubMed2026

Identification of mitochondrial energy metabolism-related candidate genes UQCR10 and NDUFA6 in pediatric tetralogy of fallot: an exploratory bioinformatics study.

BACKGROUND: Tetralogy of Fallot (TOF) is one of the most common cyanotic congenital heart diseases in infants and young children. Its molecular basis remains incompletely understood. This study aimed to identify mitochondrial energy metabolism-related candidate genes associated with pediatric TOF using public heart tissue transcriptomic datasets from the GEO database. METHODS: Datasets GSE146218 and GSE217772 were downloaded and merged, followed by batch-effect correction. Differential expression analysis was performed to identify differentially expressed genes (DEGs). Functional enrichment analysis, weighted gene co-expression network analysis (WGCNA), and protein-protein interaction (PPI) network analysis were used to prioritize candidate genes. The Comparative Toxicogenomics Database (CTD) was used as an exploratory literature-based tool to summarize gene-disease associations. RESULTS: A total of 960 DEGs were identified. Functional enrichment analyses showed that these genes were mainly enriched in mitochondrial energy metabolism-related pathways, including oxidative phosphorylation and the mitochondrial respiratory chain. WGCNA and PPI network analyses further prioritized UQCR10 and NDUFA6 as candidate genes, and both genes showed increased expression in TOF heart tissue samples. CTD analysis suggested literature-based associations between these genes and cardiovascular or developmental disease-related terms. CONCLUSION: This exploratory bioinformatics study identified UQCR10 and NDUFA6 as mitochondrial energy metabolism-related candidate genes upregulated in pediatric TOF heart tissue. These findings suggest that mitochondrial respiratory chain-related transcriptional alterations may be involved in TOF-associated myocardial remodeling or stress responses. Further experimental and clinical validation is required to confirm their biological relevance.

Humans↗

PubMed2025

Genetic analysis of Schistosoma mansoni in a low-transmission area in Brazil suggests population sharing between wild-hosts and humans and geographical isolation.

BACKGROUND: The fluke Schistosoma mansoni is the causative agent of intestinal schistosomiasis, a neglected tropical disease, and remains prevalent in certain regions of Brazil. In the municipality of Sumidouro, state of Rio de Janeiro, Brazil, a low-endemic area for S. mansoni, water rats (Nectomys squamipes) are naturally infected by this trematode. The S. mansoni populations infecting humans and water-rats in Sumidouro exhibit distinct patterns of cercarial emergence (chronotypes) and phenotypic differences between hosts. Previous studies have shown that the adaptation of S. mansoni populations to human hosts (diurnal chronotype) and water rats (nocturnal chronotype) could result in prezygotic isolation. To test this hypothesis, we employed the mitochondrial cytochrome c oxidase subunit 1 gene (MT-CO1) and microsatellite loci as genetic markers. PRINCIPAL FINDINGS: We assessed the population structure between the definitive host species and geographically distant isolates collected from two endemic localities (Pamparrão-PAM and Encanto-Soledade-ENC-SOL) in Sumidouro. Additionally, we evaluated the phylogenetic relationships between S. mansoni from Sumidouro and those from other countries. Five haplotypes of the MT-CO1 gene were identified, with haplotypes 3 and 4 exclusive to ENC-SOL, and haplotypes 1, 2, and 3 were shared between humans and water rats. Haplotype 1 was also shared with other Brazilian localities, South American countries and a single locality in West Africa. The remaining haplotypes were exclusive to Sumidouro, indicating local genetic diversity. Population structure analysis revealed no genetic differentiation associated with host species but rather geographical structuring, probably due to the sedentary habits of rodents and the limited movement of humans between localities. This finding indicates that S. mansoni populations with different chronotypes are not genetically isolated and that significant gene flow occurs between them. CONCLUSIONS: In conclusion, our findings confirm that wild rodents contribute to the maintenance of the S. mansoni life cycle in Sumidouro and can serve as indicators of local transmission hotspots.

Animals↗

PubMed2025

Molecular phylogeny of some Carangid species from the Egyptian Red Sea using cytochrome c oxidase subunit I (COI) and small (12S rRNA) mitochondrial rRNA genes.

BACKGROUND: Study of five Carangid species to estimate the degree of genetic divergence and draw phylogenetic relationships by using cytochrome c oxidase subunit I (COI), and small (12S rRNA) mitochondrial rRNA genes. AIM: This investigation was designed to evaluate genetic relationships and association analyses in the taxonomy studies of Carangid fishes using mitochondrial sequences. METHODS: The present study analyzed sequence data using two genes to estimate the relationships among five species of the family Carangidae (ray-finned fish), such as Carangoides bajad (gold-spotted trevally), Carangoides malabaricus (Malabar trevally), Caranx melampygus (Bluefin trevally), Caranx sexfasciatus (Bigeye trevally), and Scomberoides lysan (doublespotted queenfish) and to assess the phylogenetic utility of these markers. RESULTS: The classification analysis of the family Carangidae is controversial. Our study was performed to examine the phylogenetic relationships among five Carangid species using 12S rRNA and COI genes, that illustrated certain Carangidae family genera are not monophyletic that does not include all the descendants of a common ancestor (Paraphyletic) refers to a taxonomic grouping that includes a common ancestor and some, but not all, of its descendants. This means that a paraphyletic group consists of the last common ancestor and excludes certain lineages that are part of the broader group, for example, in traditional taxonomy, the class of fish is considered paraphyletic because it does not include all descendants. The data reported here may be employed in study and analysis of the phylogenetic variety and relationships among species and genera of the family Carangidae. CONCLUSION: Our results confirmed the thermostability and environmental adaptation of the five species of the Carangidae family due to higher A+T content. Our results also confirmed the earlier conclusions of other authors that several genera of the Carangidae family are not monophyletic which does not include all the descendants of a common ancestor (Paraphyletic) and demonstrated the usefulness of the 12S rRNA gene and the COI gene in the phylogenetic analysis of the Carangid species.

RNA, Ribosomal↗

PubMed2026

Mitochondrial integrated stress response activation creates a therapeutic vulnerability to MCL-1 inhibition in acute myeloid leukemia.

MCL-1 (myeloid cell leukemia-1) promotes survival and confers therapeutic resistance in acute myeloid leukemia (AML), particularly in high-risk subtypes harboring KMT2A rearrangements (KMT2A-r). Clinical trials involving patients with hematological malignancies treated with MCL-1 inhibitor monotherapy have been hampered by dose-limiting toxicity and poor response rates. Therefore, we sought to identify combinatorial treatment approaches to enhance the efficacy of MCL-1 inhibitors with the goal of improving response rates and limiting toxicities. Here, we report the inhibition of electron transport chain (ETC) complex I (CI) function as a synthetic lethal partner for MCL-1 inhibition. Co-targeting CI and MCL-1 synergistically reduces the viability in AML cell lines and patient-derived xenograft (PDX) samples in vitro, while significantly prolonging survival in mice bearing PDX AML, indicating the preclinical potential for this combinatorial therapy. These findings provide a mechanistic rationale and preclinical evidence for dual inhibition of MCL-1 and CI as a therapeutic strategy, offering a potential path to overcome resistance to single-agent MCL-1 inhibitors and improve outcomes for patients with high-risk AML. Mechanistically, we reveal that CI inhibition induces the activation of the integrated stress response, resulting in ATF4 activation downstream of the eIF2α kinase, HRI (Heme-regulated inhibitor). HRI activation via CI inhibition is dependent on the mitochondrial stress messenger, DELE1. Together, these results indicate that co-inhibition of MCL-1 and ETC CI function has the potential for improving responses in patients with KMT2A-r AML.

Humans↗

PubMed2026

Kidney mitochondrial complex I dysfunction in a juvenile rat model of diabetic ketoacidosis.

BACKGROUND: The pathobiology of acute kidney injury during diabetic ketoacidosis (DKA) is not completely understood. We hypothesized that mitochondrial function is impaired during DKA as a mechanism of acute kidney injury. METHODS: We isolated kidney samples from 4 to 5 week-old rats with normoglycemia (NG, controls; n = 7), hyperglycemia (HG; n = 5), acute DKA (DKA; n = 5), and after 24 h of DKA treatment (DKA-24; n = 5). Kidney tissue homogenates were prepared from frozen tissue for measurement of mitochondrial electron transport system (ETS) complex I + III, II + III, and IV activity and citrate synthase activity using spectrophotometry and ETS complex protein expression using Western blots. RESULTS: Mitochondrial ETS complex I + III activity (mean ± SD) exhibited a stepwise decrease from HG (113 ± 54 nmol/min/mg tissue protein) to DKA (64 ± 32; p < 0.05 compared to NG) and trended toward NG control levels (143 ± 37) in DKA-24 (135 ± 39). Mitochondrial content, including citrate synthase activity and ETS complex proteins I, II, IV, and V, did not differ between groups, except that ETS complex III increased in HG and DKA and subsequently decreased in DKA-24. CONCLUSIONS: In a juvenile rat model of DKA, increasing glycemic stress caused a reversible change in kidney mitochondrial complex I function and complex III expression. IMPACT: Acute kidney injury during diabetic ketoacidosis (DKA) increases risk of future diabetic kidney disease, but the underlying pathobiology is not understood. In a juvenile rat model of DKA, we found that increasing glycemic stress caused a reversible change in kidney mitochondrial complex I function and complex III expression. These data support further investigation to determine if mitochondrial dysfunction may contribute to DKA-related acute kidney injury.

Letter↗

PubMed2026

Relaxin-2: Shaping the Proteomic Landscape of Skeletal Muscle Physiology, Glucose Trafficking, and Mitochondrial Function in Rat.

Relaxin-2 is a hormone with robust beneficial effects on the heart and blood vessels and potential as a therapy for cardiovascular (CV) disease. Considering the interorgan communication between skeletal muscle and heart, and the relation between muscle quality/composition and CV events, we hypothesize that relaxin-2 may regulate skeletal muscle physiology and metabolism. We aim to evaluate the impact of relaxin-2 on the proteome of skeletal muscle from healthy Sprague-Dawley rats. Animals were treated with 0.4 mg/kg/day of serelaxin (recombinant form of human relaxin-2) or vehicle (PBS) for 2 weeks employing subcutaneous osmotic minipumps. Skeletal muscle protein identification and quantification were performed by LC-MS/MS using a Data-Independent Acquisition (DIA)-Sequential Window Acquisition of All Theoretical Fragment Ion Spectra (SWATH) method. SWATH/MS quantitative analysis identified that relaxin-2 significantly decreased 95 proteins and significantly increased 32 proteins in rat skeletal muscle when compared to control rats. From these, 34 proteins were associated with muscle function, myogenesis, muscle differentiation and/or regeneration, 20 are mitochondrial proteins (six from the complexes of the electron transport chain), and 10 proteins participate in glucose metabolism. Qualitative data-dependent workflow analysis identified 35 proteins exclusive to the skeletal muscle of the relaxin-2-treated group: eight proteins related to processes of skeletal muscle function (size, ion homeostasis or organization of caveolae structures and cytoskeleton) and myogenesis, and two proteins involved in muscle differentiation. Our work highlighted for the first time the role of relaxin-2 in crucial processes of muscle physiology and energetic metabolism, which could influence several processes involved in myopathy and CV.

Animals↗

PubMed2025

Cellular function of the GndA microprotein during heat shock.

Over the past 15 years, hundreds of previously undiscovered bacterial small open reading frames (sORFs) encoding microproteins of fewer than fifty amino acids have been identified. Biological functions have been ascribed to an increasing number of microproteins from intergenic regions and small RNAs, and many play integral roles in bacterial stress responses. However, despite numbering in the dozens in Escherichia coli, and hundreds in humans, same-strand frameshifted sORFs that internally overlap protein coding sequences remain understudied. To provide insight into nested genes, we characterized GndA, a frameshifted 36-amino acid microprotein nested within the 6-phosphogluconate dehydrogenase (6PGD) coding sequence. Using precise genome editing, we demonstrate independent contributions of GndA and 6PGD to cell growth at high temperature. GndA associates with membrane-associated complexes associated with electron transport and ATP generation, and supports ATP homeostasis during heat shock. Functional characterization of GndA thus adds to the catalog of bacterial microproteins that function in stress responses, while providing clear genetic evidence for the importance of an overlapping gene to cellular fitness.

6PGD↗