A Comprehensive Analysis of the Fowleria variegata (Valenciennes, 1832) Mitochondrial Genome and Its Phylogenetic Implications within the Family Apogonidae.

Controversies surrounding the phylogenetic relationships within the family Apogonidae have persisted due to the limited molecular data, obscuring the evolution of these diverse tropical marine fishes. This study presents the first complete mitochondrial genome of Fowleria variegata, a previously unrepresented genus, using high-throughput Illumina sequencing. Through a comparative mitogenomic analysis, F. variegate was shown to exhibit a typical genome architecture and composition, including 13 protein-coding, 22 tRNA and 2 rRNA genes and a control region, consistent with studies of other Apogonidae species. Nearly all protein-coding genes started with ATG, while stop codons TAA/TAG/T were observed, along with evidence of strong functional constraints imposed via purifying selection. Phylogenetic reconstruction based on maximum likelihood and Bayesian approaches provided robust evidence that F. variegata forms a basal lineage closely related to P. trimaculatus within Apogonidae, offering novel perspectives into the molecular evolution of this family. By generating new mitogenomic resources and evolutionary insights, this study makes important headway in elucidating the phylogenetic relationships and mitogenomic characteristics of Apogonidae fishes. The findings provide critical groundwork for future investigations into the drivers of diversification, speciation patterns, and adaptive radiation underlying the extensive ecological diversity and biological success of these marine fishes using phylogenomics and population genomics approaches.

Antibiotic ivermectin selectively induces apoptosis in chronic myeloid leukemia through inducing mitochondrial dysfunction and oxidative stress.

Mitochondria has been a promising target in blood cancer given their unique dependencies on mitochondrial functions compared to normal hematopoietic cells. In line with this concept, we show that an anthelminthic drug ivermectin selectively kills chronic myeloid leukemia (CML) cells via inducing mitochondrial dysfunctions and oxidative stress. Ivermectin is significantly more effective in inducing caspase-dependent apoptosis in CML cell line K562 and primary CML CD34 than normal bone marrow (NBM) CD34 cells. Ivermectin also augments in vitro and in vivo efficacy of standard CML tyrosine kinase inhibitors. Mechanistically, ivermectin inhibits respiratory complex I activity and suppresses mitochondrial respiration in K562 and CML CD34 cells. Interestingly, we demonstrate that mitochondrial respiration are lower in NBM CD34 compared to malignant CD34 cells. In addition, ivermectin also induces mitochondrial dysfunctions in NBM CD34 cells in a similar manner as in CML CD34 cells whereas NBM CD34 cells are significantly less sensitive to ivermectin than CML CD34 cells. These suggest that NBM CD34 cells are more tolerable to mitochondrial dysfunctions than CML CD34 cells. Consistently, ivermectin induces higher levels of oxidative stress and damage in CML than normal counterparts. Antioxidant NAC rescues ivermectin's effects, confirming oxidative stress as the mechanism of its action in CML. Our work provides the fundamental evidence to repurpose ivermectin for CML treatment. Our work also highlights the therapeutic value of targeting mitochondria respiration in CML.

The sensitivity of chronic myeloid leukemia CD34 cells to Bcr-Abl tyrosine kinase inhibitors is modulated by ceramide levels.

Despite BCR-ABL tyrosine kinase inhibitors (TKIs) improved outcome of patients with chronic myeloid leukemia (CML), resistance still develops when progresses to blast phase (BP). The mechanisms underlying resistance to TKIs are not well understood. In this study, we analyzed ceramide levels in CD34 cells derived from BP-CML patients and healthy donor bone marrow (BM) using liquid chromatography mass spectrometry. We found that ceramide level was significantly lower in BP-CML CD34 compared with normal BM counterparts. BP-CML CD34 ceramide(low) were more resistant to BCR-ABL TKIs compared to BP-CML CD34 ceramide(normal). Both mRNA and proteins levels of sphingomyelin synthase 1 and 2 are lower in BP-CML CD34 ceramide(low) compared to normal BM CD34 cells, suggesting that these two ceramide synthesis enzymes maybe the mechanism of how ceramide level is suppressed. Importantly, up-regulation of cellular ceramide level induces apoptosis of multiple CML cell lines and BP-CML CD34 progenitors. Combination of BCR-ABL TKIs with ceramide analog is synergistic in targeting BP-CML 34 progenitors. Collectively, our work provides evidence that down-regulation of ceramide level is involved in the resistance of BP-CML CD34 progenitors to TKIs treatment. Targeting ceramide metabolism together with BCR-ABL inhibition makes it an attractive addition to the armamentarium in BP-CML treatment.

The complete mitochondrial genome of Squalidus argentatus (Cypriniformes, Cyprinidae).

In the present study, the complete mitogenome sequence of the Cyprinid fish Squalidus argentatus (Cypriniformes, Cyprinidae) was determined. The mitogenome, consisting of 16,609 base pairs (bp), was characterized by the typical vertebrate mitochondrial gene arrangement, including 13 protein-coding, 22 transfer RNAs, 2 ribosomal RNAs genes and a noncoding control region. Control region (CR), of 931 bp in length, was located between tRNA(Pro) and tRNA(Phe). The overall base composition of S. argentatus was 30.45% for A, 16.70% for G, 25.62% for T and 27.24% for C, with a slight AT bias of 56.07%.