Sedum sarmentosum Bunge is a perennial succulent plant of medicinal significance within the Crassulaceae family. To investigate its mitochondrial genome (mitogenome), structure, gene composition, and evolutionary implications, we assembled the complete mitogenome and plastid genome (ptgenome) of S. sarmentosum using high-fidelity sequencing data. The resulting mitogenome is a circular DNA molecule of 156,727 bp with a GC content of 45.30%, encoding 30 protein-coding genes (PCGs), eight tRNAs, and two rRNAs. Analyses identified 78 simple sequence repeats, two tandem repeats, and 30 dispersed repeats. A total of 617 potential RNA-editing sites were predicted, predominantly occurring at the second codon positions of mitochondrial PCGs. In addition, 18 mitochondrial plastid DNA transfer events were identified between the mitochondrial and chloroplast genomes, which included both tRNA and partial protein-coding gene segments. Moreover, the regional boundaries of chloroplasts of S. sarmentosum was identified, consisting of a large single-copy (LSC) region (81,798 bp), a small single-copy (SSC) region (16,671 bp), and two inverted repeat (IR) regions (25,778 bp each). Phylogenetic analyses based on mitogenomes of 26 species revealed that S. sarmentosum is closely related to members of the Rhodiola genus within Crassulaceae, providing new insights into evolutionary relationships among Saxifragales. Furthermore, codon usage bias, selection pressure analysis, and nucleotide diversity assessments uncovered lineage-specific patterns of molecular evolution, highlighting the balance between purifying and positive selection in shaping mitochondrial gene divergence. Altogether, this study contributes to our understanding of mitogenomic architecture, evolutionary adaptation, and phylogenetic placement of S. sarmentosum , and offers a valuable genomic resource for future studies in plant evolution, functional genomics, and molecular breeding.

Heart failure (HF) represents the terminal stage of many cardiovascular diseases. Doxorubicin (DOX) can induce HF through oxidative stress (OS), inflammation, and apoptosis. Ginkgetin (GK) has potential cardioprotective effects, but its underlying mechanisms remain unclear. This study investigated the protective effects of GK against DOX-induced HF and explored its mechanisms, focusing on mitochondrial function and related signaling pathways. In vivo and in vitro experimental models. HF was induced by DOX in mice and H9c2 cardiomyocytes. Cardiac function, myocardial injury, OS, inflammation, and apoptosis were assessed using echocardiography, biochemical assays, enzyme-linked immunosorbent assay, histopathology, immunofluorescence, and Western blot. Mitochondrial function was evaluated via transmission electron microscopy, RT-qPCR, and Seahorse analysis. Compound C was applied to verify the involvement of the adenosine monophosphate-activated protein kinase (AMPK)/Sirt1/nuclear factor-κB (NF-κB) pathway. GK markedly improved DOX-induced cardiac dysfunction and myocardial injury, reduced cardiac injury markers and inflammatory cytokines, and alleviated fibrosis, hypertrophy, apoptosis, and reactive oxygen species accumulation. GK restored superoxide dismutase activity, decreased malondialdehyde levels, increased glutathione and ATP, and preserved mitochondrial structure and respiratory function. GK upregulated AMPK and Sirt1, inhibited NF-κB activation, and regulated apoptosis-related proteins, whereas Compound C reversed these effects. GK protects against DOX-induced HF by activating AMPK/Sirt1 and inhibiting NF-κB signaling, thereby mitigating OS, inflammation, apoptosis, and mitochondrial dysfunction.

Mitochondrial dysfunction affects skeletal muscle (SkM) function and is critical in the etiology of age-related sarcopenia. The sirtuin 1-PGC1α pathway is a key regulator of mitochondrial mass, structure, and function. However, pathway activity decreases with aging. Cacao flavanols show promise in their ability to activate mitochondrial pathways. We evaluated the capacity of the flavanol (+)-epicatechin (+Epi) to stimulate such a pathway and favorably impact mitochondrial and oxidative stress (OS)-associated endpoints in aged SkM. Using 23-month-old male Sprague-Dawley rats, an 8-week oral administration of +Epi (1 mg/kg/day) was implemented, and results were compared versus vehicle-treated controls. Assessments included the nicotinamide adenine dinucleotide (NAD)/sirtuin 1/PGC1α pathway, acetylated proteins levels, mitochondrial function and biogenesis, as well as OS-related endpoints in SkM. +Epi increased the NAD/NADH ratio, activation of sirtuin 1, the deacetylation of nuclear protein content, including that of PGC1α. Also, +Epi induced increases of TFAM and NRF1 mRNA levels, deacetylation of mitochondrial complex I and V, increases in complex I activity, sirtuin 3, complexes I and V, mitofilin, and TFAM protein levels. SkM citrate synthase activity and ATP content increased with +Epi. OS markers in proteins and lipids were reduced, while buffering systems (superoxide dismutase 2 and catalase protein and activities) increased. In white blood cells, we documented serial reductions in mitochondrial DNA content and citrate synthase activity with aging, which were either fully or partially reversed with +Epi. Results demonstrate that +Epi treatment yields positive effects on mitochondrial biogenesis and function, leading to decreased OS and improved SkM bioenergetics in aged rats.

Pancreatic β-cells are uniquely dependent on mitochondrial metabolism to couple glucose sensing to insulin secretion, a process impaired in diabetes. Mitochondrial fission process 1 (MTFP1) is an inner mitochondrial membrane protein that plays pleiotropic, tissue-specific roles in mitochondrial function and dynamics. Our previous work has identified Mtfp1 mRNA as a target for miR-125b, a microRNA that negatively regulates insulin secretion from β-cells. Nevertheless, the function of MTFP1 in these cells remained unexplored. Here, we show that MTFP1 is essential for normal glucose-stimulated insulin secretion (GSIS) in mouse and human cell lines and islets, and that mice with β-cell-specific elimination of MTFP1 develop glucose intolerance. Whereas β-cell survival and mitochondrial content were unaffected, oxidative phosphorylation and ATP production were sharply lowered. These changes were accompanied by disruption of mitochondrial cristae structure and a reduced contact surface with the endoplasmic reticulum, providing a mechanistic basis for defective stimulus-secretion coupling. Conversely, MTFP1 overexpression in mouse and human islets sufficed to improve mitochondrial respiration and GSIS. Finally, MTFP1 downregulation blocked the positive effects of miR-125b elimination in GSIS and mitochondrial respiration, unveiling MTFP1 as a downstream effector of miR-125b. Together, our findings identify MTFP1 as a critical regulator of β-cell mitochondrial architecture and function, necessary for efficient insulin secretion and glucose homeostasis, and a potential therapeutic target to enhance β-cell bioenergetic resilience in diabetes.

LRRN3 protects dopaminergic neurons by inhibiting glycolysis in Parkinson's disease.

Tirzepatide enhances liver structural integrity by promoting mitochondrial dynamics and mitophagy via PINK1/PRKN and SIRT3/NRF2 pathways in an obese-diabetic-menopausal mouse model.

Trimethylamine-N-oxide disrupts spermatogenesis by inducing mitochondrial oxidative stress injury through Hippo signaling.

Beyond the cold: New insights for neuroprotection and neurorecovery from functional genomics.

Abstract This study investigates the phylogenetic relationships of extant crocodiles and the population structure of the saltwater crocodile (Crocodylus porosus). We combined mitochondrial genomes from museum specimens with genetic data from modern samples to reconstruct the evolutionary history of the saltwater crocodile and clarify the identity of the extinct Seychelles crocodile. Mitochondrial genomes were sequenced for 11 museum specimens of Crocodylus halli, C. niloticus, C. novaeguineae, C. palustris and C. porosus, including the Seychelles crocodile. In addition, the mitochondrial control and ND4 regions were analysed for 187 and 13 C. porosus individuals, respectively. This study provides the most comprehensive Crocodylus phylogeny to date, establishes the phylogenetic placement of the extinct Seychelles crocodile as a distant population of the saltwater crocodile and provides no mitochondrial support for C. halli as a distinct species from C. novaeguineae. Nineteen haplotypes were identified among C. porosus samples, showing no clear mitochondrial geographic structure. However, this probably reflects the limited resolution of mitochondrial DNA rather than true genetic homogeneity, consistent with nuclear genomic studies revealing strong regional differentiation. Our results highlight the need for conservation strategies that recognize the broad genetic connectivity of C. porosus populations rather than emphasizing subspecies distinctions.

Lysosomes are critical for maintaining cellular homeostasis and nutrient availability, yet how tumor cells survive under lysosomal inhibition remains unclear. Here, we revealed that inhibiting lysosome function with chloroquine unexpectedly stimulated glucose uptake across various cancer cells. This effect was driven by sterol regulatory element-binding protein 1 (SREBP-1), a key lipogenic transcription factor, which specifically increased the expression of glucose transporters GLUT3 and GLUT6, enhancing glucose uptake and macromolecule synthesis. Elevated glucose, induced by chloroquine, stabilized SREBP cleavage-activating protein (SCAP), the activator of SREBP-1, further amplifying its activity and contributing to tumor resistance to lysosome inhibition. Disrupting this SREBP-1-glucose uptake feedforward loop by combining chloroquine with inhibitors of glucose transporters, SREBP-1, or lipogenic enzymes induced a synergistic antitumor effect in squamous cell and adenocarcinoma lung cancer patient-derived organoids and xenografts. This combination impaired mitochondrial structure and function, inducing apoptotic tumor cell death. Our study uncovers a role for SREBP-1 in regulating glucose metabolism and provides a promising therapeutic strategy that combines lysosome inhibition with glucose transporter or lipogenic enzyme inhibition for effective cancer treatment.

ABSTRACTPartial reprogramming has emerged as a promising strategy to reset the epigenetic landscape of aged cells towards more youthful profiles. Recent advancements have included the development of chemical reprogramming cocktails that can lower the epigenetic and transcriptomic age of cells and upregulate mitochondrial biogenesis and oxidative phosphorylation. However, the ability of these cocktails to affect biological age in a mammalian aging model has yet to be tested. Here, we have characterized the effects of partial chemical reprogramming on mitochondrial structure and function in aged mouse fibroblasts and tested its in vivo efficacy in genetically diverse male UM‐HET3 mice. This approach increases the size of mitochondria, alters cristae morphology, causes an increased fusing of mitochondrial networks, and speeds up movement velocity. At lower doses, the chemical reprogramming cocktail can be safely administered to middle‐aged mice using implantable osmotic pumps, albeit with no effect on the transcriptomic age of kidney or liver tissues and only a modest effect on the expression of OXPHOS complexes. However, at higher doses, the cocktail causes a drastic reduction in body weight necessitating euthanasia. In the livers and kidneys of these animals, we observe significant increases in lipid droplet accumulation, as well as changes in mitochondrial morphology in the livers that are associated with mitochondrial stress. Thus, partial chemical reprogramming may induce mitochondrial stress and lead to significant lipid accumulation, which may cause toxicity and hinder the rejuvenation of cells and tissues in aged mammals.

Neuronal mitochondria display distinct morphologies across compartments, with dendritic mitochondria being elongated and axonal ones shorter, and their morphologies are dynamically changed via fusion and fission machineries. Mitochondrial structural abnormalities are common in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, yet systematic evaluation of therapeutic targets remains limited. Here, we tested key mitochondrial shape regulators, mitofusin 1/2 for fusion and Mff/Fis1 for fission, in an α-synucleinopathy model. Using MitoVis, a deep learning-based neuronal mitochondrial image analysis tool, we achieved rapid, compartment-specific analysis of mitochondrial morphologies. Among all interventions, Fis1 knockdown most effectively protected mitochondrial structure to control levels without inducing over-elongation of axonal mitochondria, which was linked to abnormal Ca2+ dynamics. While all manipulations preserved dendritic spine loss, Fis1 optimally maintained axonal mitochondrial function. These findings demonstrate a high-throughput screening approach for mitochondrial regulators and highlight Fis1 as a promising preventive/therapeutic target. Our results support targeting mitochondrial morphology as a viable strategy for treating α-synucleinopathy and potentially other mitochondria-related neurodegenerative diseases.

Cantharidic acid (CA) is a cantharidin analog and has antitumor effects. This study aimed to investigate the antitumor activity of CA against colorectal cancer (CRC) and the underlying mechanisms of this activity. The impact of CA on the viability of the normal FHC cell line was evaluated by the CCK-8 assay. The malignant behavior of CRC cells was determined using the CCK-8 assay, colony formation assay, Transwell assay, and an LDH commercial kit. The surviving and apoptotic cell numbers were examined via flow cytometry and calcein-AM/PI staining. The ultrastructure of the mitochondria was observed, and the concentration of mtDNA was detected via RT-qPCR. A subcutaneous xenograft tumor model in nude mice was established, and pathological staining was used to assess apoptosis and changes in protein expression. Western blotting was used to evaluate the levels of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1)/glutathione peroxidase 4 (GPX4) pathway-related proteins and mitochondrial damage-related proteins. CA did not significantly affect FHC viability but was able to reduce CRC cell viability, decrease colony-forming ability, inhibit migration and invasion, and induce apoptosis. CA treatment disrupted mitochondrial morphology and structure and caused a decrease in mitochondrial membrane potential, ATP production, and mtDNA concentration. Treatment with Mito-TEMPO (a mitochondrion-targeted antioxidant) reversed the effects of CA treatment on the above metrics. Furthermore, CA blocked the Nrf2/HO-1/GPX4 pathway, whereas the Nrf2 agonist TBHQ alleviated CA-induced mitochondrial dysfunction. CA treatment decreased the volume and mass of tumor tissue, inhibited cell proliferation, and promoted apoptosis. Notably, CA also led to mitochondrial dysfunction in vivo, which was effectively mitigated by TBHQ. CA blocks the Nrf2/HO-1/GPX4 pathway, causing mitochondrial dysfunction and apoptosis, and thus inhibits the malignant progression of CRC. CA has potential as a therapeutic agent for CRC.

To observe the effect of electroacupuncture (EA) on mitochondrial fission/fusion in rats with learning-memory impairment induced by cerebral ischemia-reperfusion (CI/R), so as to explore its potential neuroprotective mechanisms against the ischemic reperfusion injury of hippocampal neurons. Male SD rats were randomly divided into normal, sham-operation, model, and EA groups, with 12 rats in each group. The CI/R model was established by middle cerebral artery occlusion and reperfusion by using the intraluminal suture method. After successful modeling, rats in the EA group received EA (2 Hz/10 Hz, 6 V) at "Shenting"(GV24) and "Baihui" (GV20) for 30 min, once daily for 14 consecutive days. The rats' learning-memory ability was evaluated using the novel object recognition test and Morris water maze test. The cerebral infarct volume was assessed by 2, 3, 5-triphenyltetrazolium chloride (TTC) staining. Hippocampal neuronal morphology was examined by HE staining, and the mitochondrial morphology and structure of hippocampal neurons were observed using transmission electron microscopy. The adenosine triphosphate (ATP) content in the hippocampal tissue was measured using colorimetry, and mitochondrial DNA (mtDNA) copy number was detected by qPCR. The relative protein and mRNA expression levels of mitochondrial fusion proteins 1/2 (MFN1/2), optic atrophy protein 1 (OPA1), dynamin-related protein 1 (DRP1), and fission protein 1 (FIS1) in the hippocampal tissue were detected by Western blot and qPCR respectively. No significant differences were found between the normal and sham-operation groups in all the indices. Compared with the sham-operation group, the model group exhibited a significant increase in the escape latency of Morris water maze test from the 3rd to the 5th day, brain infarction volume, expression levels of DRP1 and FIS1 protein and mRNA (P<0.01, P<0.05), and a significant decrease in the novel object recognition index, crossing number of the original target platform in Morris water maze test, copy number of mtDNA, ATP content, and the expression levels of MFN1, MFN2, and OPA1 protein and mRNA (P<0.01, P<0.05). In comparison with the model group, both the increased levels of the escape latency, brain infarction volume, expressions of DRP1 and FIS1 protein and mRNA, and the decreased levels of the novel object recognition index, crossing number of the original target platform, copy number of mtDNA, ATP content, and the expressions of MFN1, MFN2, and OPA1 protein and mRNA were reversed in the EA group (P<0.01, P<0.05). Histological examination showed that in the model group, the hippocampal neurons were loosely arranged, with extensive vacuolar degeneration and necrosis, swollen and ruptured mitochondria, irregular mitochondrial membrane, and disappearance of cristae, while in the EA group, hippocampal neurons were closely arranged and relative intact in the morphology, with relatively complete mitochondria, and clear cristae. EA can improve the learning-memory ability in CI/R rats which may be related to its functions in inhibiting the mitochondrial fission and promoting mitochondrial fusion, thus maintaining mitochondrial function and structural stability.

Mitochondria are essential organelles involved in metabolism, energy production, and cell signaling. Assessing mitochondrial morphology is key to tracking cell metabolic activity and function. Quantifying these structural changes may also provide critical insights into disease pathogenesis and therapeutic responses. This work details the development and validation of a novel, quantitative image analysis pipeline for the characterization and classification of dynamic mitochondrial morphologies. Utilizing high-resolution confocal microscopy, the pipeline integrates first-order statistics (FOS) and a comprehensive suite of gray-level texture analyses, including gray level co-occurrence matrix (GLCM), gray level run length matrix (GLRLM), gray level dependence matrix (GLDM), gray level size zone matrix (GLSZM), and neighboring gray tone difference matrix (NGTDM) with machine learning approaches. The method’s efficacy in objectively differentiating key mitochondrial structures—fibers, puncta, and rods—which are critical indicators of cellular metabolic and activation states is demonstrated. Our open-source pipeline provides robust quantitative metrics for characterizing mitochondrial variation.

Continuous human-mediated introduction of colonies and queens promotes genetic introgression and reshapes the genetic diversity and structure of local honeybee populations. According to reports, multiple non-native honeybee colonies and queens have been introduced into the DL region, leading to continuous genetic introgression. Here, we assessed the effects of continuous introgression on indigenous Apis cerana in the DL region using mtDNA and genome-wide SNP markers. We sequenced the mitochondrial tRNA leu-COII from 217 individuals sampled at 7 DL sites and identified 26 haplotypes defined by 18 polymorphic sites. The ΦST values indicated no internal differentiation within the Apis cerana populations in the DL region. Phylogenetic, network, ABBA-BABA test, and f3 statistic suggested introgression from both northern and southern sources. The f4-ratio indicates that approximately 16% of the ancestry in the DL group is derived from the Aba group. Genetic diversity varied widely within the DL region (Hd: 0.2907-0.8220; π: 0.0009-0.0038; K: 0.3140-1.3980), indicating different stages of introgression. The genetic structure within the DL group appears to be unstable, necessitating long-term monitoring of evolutionary processes and genetic diversity dynamics in A. c. cerana for further insights.

Organ toxicity of Paris polyphylla in mice and the underlying hepatotoxic mechanism uncovered by an integrated network toxicology and transcriptomics.

Fine particulate matter (PM2.5)-induced ovarian damage has attracted widespread attention, but differences in cytotoxicity and underlying mechanisms of water-soluble (WS-PM2.5) and water-insoluble (WIS-PM2.5) fractions are unclear. To investigate potential effects of PM2.5 from livestock farming environments on animal ovaries, PM2.5 samples were collected from large-scale cattle barns. There were significant differences between fractions regarding elemental composition, proportion of water-soluble ions, polycyclic aromatic hydrocarbon content, and endotoxin concentrations. Based on transcriptome sequencing results, in a cowshed PM2.5 exposure model (rats), differentially expressed ovarian mRNAs were significantly enriched in signaling pathways such as cytokine interaction and the Hippo pathway, with the expression of thioredoxin-interacting protein (Txnip) significantly increased. In vitro (primary rat ovarian granulosa cells), short-term exposure to WS-PM2.5 (12 h) significantly induced inflammatory factor release, acute oxidative stress, mitochondrial dysfunction, and intracellular Ca2+ overload, with characteristics of rapid acute injury. However, extended (24 h) WIS-PM2.5 exposure had greater disruptive effects on estrogen homeostasis, intracellular enzyme release (LDH), and mitochondrial structure (subacute characteristics). Furthermore, downregulating Txnip expression via inhibitors effectively mitigated cowshed PM2.5-induced ovarian granulosa cell toxicity, oxidative stress, and mitochondrial and hormonal dysfunction. In summary, solubility of cowshed PM2.5 components affected cytotoxic characteristics, and Txnip was a key factor linking oxidative stress to granulosa cell damage. The study provided a mechanistic basis and potential targets for preventing and controlling PM2.5-induced ovarian damage in livestock environments.

Anorexia nervosa (AN) is a severe eating disorder associated with extreme weight loss, hyperactivity, and amenorrhea. Neuroimaging studies revealed brain atrophy and disruption of white matter integrity in the corpus callosum (CC) of patients with AN. However, the underlying pathophysiological mechanisms remain unclear. Emerging evidence indicates that starvation induces changes in mitochondrial metabolism and dynamics. We hypothesize that disturbances in white matter integrity arise from modifications in oligodendrocytes, associated with changes in the morphology of myelinated fibers and mitochondrial structure. The starvation-induced hyperactivity (SIH) model was used, in which mice received a restricted daily amount of food in combination with free access to a running wheel. A body weight loss of 25% was maintained over 2 weeks, followed by a 3-week refeeding phase. Oligodendrocyte density and staining intensity of oligodendrocyte lineage transcription factor 2 (OLIG2) in the CC were analyzed using immunohistochemical staining. Morphometric investigation of myelinated fibers and mitochondria was conducted by transmission electron microscopy (TEM) analysis. Starvation led to decreased oligodendrocyte density and reduced anti-OLIG2 staining intensity in the CC, which was reversible following refeeding. Additionally, starvation induced a decrease in axonal caliber and an increase in mitochondrial density in the white matter, accompanied by a reduction of mitochondrial area. The findings suggest that oligodendroglial and axonal alterations, alongside disrupted mitochondrial dynamics, impair structural integrity in the white matter and contribute to the pathophysiology of AN.

Cynomolgus macaques are widely used in biomedical research, yet the hybridisation between the subspecies M. f. fascicularis (Mff) and M. f. aurea (Mfa), and introgression from another species M. mulatta (Mm) may affect the research outcomes. DNA barcoding targeting COI mtDNA, as well as phylogenetic, pairwise distance and statistical analyses were employed to examine the relationships between Mff, Mfa and Mm using 52 newly sequenced and 59 public DNA barcodes representing 17 Macaca taxa and seven species groups. DNA barcoding delineated the Macaca taxa, revealing genetic distinctions between Mff and Mfa greater than between Mff and Mm, as well as delineating geographical populations. This underscores the need for verification of laboratory individuals, besides genetic management of breeding colonies, as genetic differences can influence disease susceptibility and drug trial outcomes. DNA barcoding offers a rapid, cost-effective tool to ensure appropriate selection and genetic management of laboratory individuals used in biomedical research.