The MICOS complex (mitochondrial contact site and cristae organizing system) is essential for mitochondrial inner membrane organization and mitochondrial membrane contacts, however, the molecular regulation of MICOS assembly and the physiological functions of MICOS in mammals remain obscure. Here, we report that Mic60/Mitofilin has a critical role in the MICOS assembly, which determines the mitochondrial morphology and mitochondrial DNA (mtDNA) organization. The downregulation of Mic60/Mitofilin or Mic19/CHCHD3 results in instability of other MICOS components, disassembly of MICOS complex and disorganized mitochondrial cristae. We show that there exists direct interaction between Mic60/Mitofilin and Mic19/CHCHD3, which is crucial for their stabilization in mammals. Importantly, we identified that the mitochondrial i-AAA protease Yme1L regulates Mic60/Mitofilin homeostasis. Impaired MICOS assembly causes the formation of 'giant mitochondria' because of dysregulated mitochondrial fusion and fission. Also, mtDNA nucleoids are disorganized and clustered in these giant mitochondria in which mtDNA transcription is attenuated because of remarkable downregulation of some key mtDNA nucleoid-associated proteins.Together, these findings demonstrate that Mic60/Mitofilin homeostasis regulated by Yme1L is central to the MICOS assembly, which is required for maintenance of mitochondrial morphology and organization of mtDNA nucleoids. Mitochondria have a key role in oxidative phosphorylation and related cellular metabolism, in energy conversion, in programmed cell death, in cell growth and in diseases. Mitochondrial outer and inner membranes strongly differ in architecture and functions. The mitochondrial outer membrane forms a barrier to cytosol, and contains channels and the translocases of outer membrane, which is the main protein entry gate of mitochondria. 1,2 In contrast, the mitochondrial inner membrane consists of two morphologically distinct regions: the inner boundary membrane is in close proximity to the outer membrane and the cristae membranes that are large tubular invaginations. [3][4][5][6][7][8] The mitochondrial inner boundary and cristae membrane are physically separated by cristae junctions, which are narrow tubular or slot-like structure. 4,9 The mitochondrial cristae are arranged in regular arrays and are the main sites of ATP production in the mitochondria, but the molecules that are associated with the maintenance of cristae architecture still remain elusive. Recently, several groups identified a large protein complex, MICOS complex (mitochondrial contact site and cristae organizing system; previously named MINOS, MitOS, Mitofilin or Fcj1 complex ), that has a crucial role in the formation of cristae junctions, contact sites to the outer membrane, and the organization of inner membrane. [10][11][12][13][14] In yeast, MICOS consists of at least six subunits: Mic60 (Fcj1), Mic10 (Mio10/Mcs10/Mos1), Mic19 (Aim13/Mcs19), Mic26 (Mio27/Mcs29/Mos2), Mic12 (Aim5/ Msc12) and Mic27 (Aim37/Mcs27). In mammals, five s...

A Sri Lankan indica rice (Oryza sativa L.) cultivar Rathu Heenati was found to be resistant to all the four biotypes of the brown planthopper (BPH) (Nilaparvata lugens Stål). In the present study, we constructed a linkage map to identify the locus (loci) for the BPH resistance genes, using an F 2 population from a cross between Rathu Heenati and a susceptible cultivar 02428. Insect resistance was evaluated using 156 F 2:3 lines and the genotype of each F 2 plant was inferred from the phenotype of the corresponding F 2:3 lines. Three loci detected by QTL (quantitative trait locus) analysis, were assigned to chromosomes 3, 4 and 10. The phenotypic variance of the three QTLs indicated that the QTL on chromosome 4 is a major BPH resistance gene in Rathu Heenati. Through linkage analysis, it was found that this BPH resistance gene was located between two SSR markers RM8213 and RM5953 on the short arm of chromosome 4, with map distances of 3.6 cM and 3.2 cM, respectively. This gene, tentatively designated as Bph17, should be useful for the breeding of varieties resistant to BPH in a marker-assisted selection (MAS) program.

Hypoxia in a solid tumor microenvironment (TME) can lead to the overexpression of hypoxia-inducible factor-1α (HIF-1α), which correlates to tumor metastasis. Reactive oxygen species (ROS) induced tumor cell apoptosis is becoming a promising method in tumor treatment. Currently, the ROS generating systems, e.g., photodynamic treatment and sonodynamic treatment, highly depend on oxygen (O 2 ) in the tumor microenvironment (TME). However, the level of O 2 in TME is too low to produce enough ROS. Herein, we developed an ultrasmall DSPE-PEG 2000 coated barium titanate nanoparticle (P-BTO) for tumor treatment based on ultrasound triggered piezocatalysis and water splitting. Interestingly, irradiated by ultrasound, the surface of ultasmall P-BTO nanoparticles produced imbalance charges, which induced a cascade of redox reaction processes to simultaneously generate ROS and O 2 , the latter one was hardly generated in large-sized barium titanate nanoparticles. The assynthesized P-BTO reached the highest accumulation in the tumor site at 4 h after intravenous injection. The results showed that the produced O 2 significantly alleviated the hypoxia of TME to down-regulate the expression of HIF-1α, and the produced ROS can efficiently kill tumor cells. Moreover, the tumor metastasis was also inhibited, providing a different way to treat triple-negative breast cancer, which was easily metastatic and lacked effective treatments in the clinic.

Protein modification by ubiquitin and ubiquitin-like proteins (UBLs) regulates numerous biological functions. The UFM1 system, a novel UBL conjugation system, is implicated in mouse development and hematopoiesis. However, its broad biological functions and working mechanisms remain largely elusive. CDK5RAP3, a possible ufmylation substrate, is essential for epiboly and gastrulation in zebrafish. Herein, we report a crucial role of CDK5RAP3 in liver development and hepatic functions. Cdk5rap3 knockout mice displayed prenatal lethality with severe liver hypoplasia, as characterized by delayed proliferation and compromised differentiation. Hepatocyte-specific Cdk5rap3 knockout mice suffered post-weaning lethality, owing to serious hypoglycemia and impaired lipid metabolism. Depletion of CDK5RAP3 triggered endoplasmic reticulum stress and activated unfolded protein responses in hepatocytes. We detected the in vivo interaction of CDK5RAP3 with UFL1, the defined E3 ligase in ufmylation. Notably, loss of CDK5RAP3 altered the ufmylation profile in liver cells, suggesting that CDK5RAP3 serves as a novel substrate adaptor for this UBL modification. Collectively, our study identifies CDK5RAP3 as an important regulator of ufmylation and suggests the involvement of ufmylation in mammalian development.

Poly(dimethylsiloxane) (PDMS) has been widely utilized in micro-electromechanical systems (MEMS) and implantable devices. To improve the hemocompatibility of a PDMS-based implant, a facile technique was developed by modifying PDMS with a hyaluronic acid (HA) and polydopamine (PDA) composite (HA/PDA). Under appropriate ratio of HA to PDA, platelet adhesion and activation were considerably reduced on modified PDMS substrates, indicating an enhanced hemocompatibility compared to native PDMS or those coated with HA or PDA solely. HA/PDA coating also posed minimal cytotoxicity on the adhesion and proliferation of endothelial cells (HUVECs). The anti-inflammation effect of the modified PDMS surface was characterized based on the expression of critical cytokines in adherent macrophages. This study revealed that the hemocompatibility, cytotoxicity, and anti-inflammation properties could be tailored conveniently by adjusting the ratio of HA and PDA composite on the modified PDMS surface, which has an exceptional potential as the core or packaging material for constructing implantable devices in biomedical applications.