Mitochondrial fragmentation due to imbalanced fission and fusion of mitochondria is a prerequisite for mitophagy, however, the exact "coupling" of mitochondrial dynamics and mitophagy remains unclear. We have previously identified that FUNDC1 recruits MAP1LC3B/LC3B (LC3) through its LC3-interacting region (LIR) motif to initiate mitophagy in mammalian cells. Here, we show that FUNDC1 interacts with both DNM1L/DRP1 and OPA1 to coordinate mitochondrial fission or fusion and mitophagy. OPA1 interacted with FUNDC1 via its Lys70 (K70) residue, and mutation of K70 to Ala (A), but not to Arg (R), abolished the interaction and promoted mitochondrial fission and mitophagy. Mitochondrial stress such as selenite or FCCP treatment caused the disassembly of the FUNDC1-OPA1 complex while enhancing DNM1L recruitment to the mitochondria. Furthermore, we observed that dephosphorylation of FUNDC1 under stress conditions promotes the dissociation of FUNDC1 from OPA1 and association with DNM1L. Our data suggest that FUNDC1 regulates both mitochondrial fission or fusion and mitophagy and mediates the "coupling" across the double membrane for mitochondrial dynamics and quality control.

• Acute myeloid leukemia (AML) patients present an altered glucose metabolism signature.• A panel of 6 metabolite biomarkers involved in glucose metabolism are identified with prognostic value for cytogenetically normal AML.Acute myeloid leukemia (AML) is a group of hematological malignancies with high heterogeneity. There is an increasing need to improve the risk stratification of AML patients, including those with normal cytogenetics, using molecular biomarkers. Here, we report a metabolomics study that identified a distinct glucose metabolism signature with 400 AML patients and 446 healthy controls. The glucose metabolism signature comprises a panel of 6 serum metabolite markers, which demonstrated prognostic value in cytogenetically normal AML patients. We generated a prognosis risk score (PRS) with 6 metabolite markers for each patient using principal component analysis. A low PRS was able to predict patients with poor survival independently of wellestablished markers. We further compared the gene expression patterns of AML blast cells between low and high PRS groups, which correlated well to the metabolic pathways involving the 6 metabolite markers, with enhanced glycolysis and trichloracetic acid cycle at gene expression level in low PRS group. In vitro results demonstrated enhanced glycolysis contributed to decreased sensitivity to antileukemic agent arabinofuranosyl cytidine (Ara-C), whereas inhibition of glycolysis suppressed AML cell proliferation and potentiated cytotoxicity of Ara-C. Our study provides strong evidence for the use of serum metabolites and metabolic pathways as novel prognostic markers and potential therapeutic targets for AML. (Blood. 2014;124(10):1645-1654

Gold nanoparticles have potential applications in biomedicine, but one of the important concerns is about their safety. Most toxicology data are derived from in vitro studies and may not reflect in vivo responses. Here, an animal toxicity study of 13.5 nm gold nanoparticles in mice is presented. Animal survival, weight, hematology, morphology, and organ index are characterized at different concentrations (137.5-2200 µg/kg) over 14-28 days. The results show that low concentrations of gold nanoparticles do not cause an obvious decrease in body weight or appreciable toxicity, even after their breakdown in vivo. High concentrations of gold nanoparticles induced decreases in body weight, red blood cells, and hematocrit. It was also found that gold nanoparticles administered orally caused significant decreases in body weight, spleen index, and red blood cells. Of the three administration routes, the oral and intraperitoneal routes showed the highest toxicity, and the tail vein injection showed the lowest toxicity. Combining the results of all of these studies, we suggest that targeted gold nanopartices by tail vein injection may be suitable for enhancement of radiotherapy, photothermal therapy, and related medical diagnostic procedures.

Strategies to enhance response to poly(adenosine diphosphate–ribose) polymerase inhibitor (PARPi) in primary and acquired homologous recombination (HR)–proficient tumors would be a major advance in cancer care. We used a drug synergy screen that combined a PARPi, olaparib, with 20 well-characterized epigenetic drugs and identified bromodomain and extraterminal domain inhibitors (BETis; JQ1, I-BET762, and OTX015) as drugs that acted synergistically with olaparib in HR-proficient cancer cells. Functional assays demonstrated that repressed BET activity reduces HR and thus enhances PARPi-induced DNA damage in cancer cells. We also found that inhibition or depletion of BET proteins impairs transcription of BRCA1 and RAD51, two genes essential for HR. Moreover, BETi treatment sensitized tumors to PARP inhibition in preclinical animal models of HR-proficient breast and ovarian cancers. Finally, we showed that the BRD4 gene was focally amplified across 20 types of common cancers. Combination with BETi could greatly expand the utility of PARP inhibition to patients with HR-proficient cancer.

SUMMARY Disparities in cancer care have been a long-standing challenge. We estimated the genetic ancestry of The Cancer Genome Atlas patients, and performed a pan-cancer analysis on the influence of genetic ancestry on genomic alterations. Compared with European Americans, African Americans (AA) with breast, head and neck, and endometrial cancers exhibit a higher level of chromosomal instability, while a lower level of chromosomal instability was observed in AAs with kidney cancers. The frequencies of TP53 mutations and amplification of CCNE1 were increased in AAs in the cancer types showing higher levels of chromosomal instability. We observed lower frequencies of genomic alterations affecting genes in the PI3K pathway in AA patients across cancers. Our result provides insight into genomic contribution to cancer disparities.

Establishment of implantation in pig is accompanied by a coordinated interaction between the maternal uterine endometrium and conceptus development. We investigated the expression profiles of endometrial tissue on Days 9, 12 and 15 of pregnancy and on Day 12 of non-pregnancy in Yorkshire, and performed a comprehensive analysis of long non-coding RNAs (lncRNAs) in endometrial tissue samples by using RNA sequencing. As a result, 2805 novel lncRNAs, 2,376 (301 lncRNA and 2075 mRNA) differentially expressed genes (DEGs) and 2149 novel transcripts were obtained by pairwise comparison. In agreement with previous reports, lncRNAs shared similar characteristics, such as shorter in length, lower in exon number, lower at expression level and less conserved than protein coding transcripts. Bioinformatics analysis showed that DEGs were involved in protein binding, cellular process, immune system process and enriched in focal adhesion, Jak-STAT, FoxO and MAPK signaling pathway. We also found that lncRNAs TCONS_01729386 and TCONS_01325501 may play a vital role in embryo pre-implantation. Furthermore, the expression of FGF7, NMB, COL5A3, S100A8 and PPP1R3D genes were significantly up-regulated at the time of maternal recognition of pregnancy (Day 12 of pregnancy). Our results first identified the characterization and expression profile of lncRNAs in pig endometrium during pre-implantation phases.

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Mitophagy is an essential process for mitochondrial quality control and turnover. It is activated by two distinct pathways, one dependent on ubiquitin and the other dependent on receptors including FUNDC1. It is not clear whether these pathways coordinate to mediate mitophagy in response to stresses, or how mitophagy receptors sense stress signals to activate mitophagy. We find that the mitochondrial E3 ligase MARCH5, but not Parkin, plays a role in regulating hypoxia-induced mitophagy by ubiquitylating and degrading FUNDC1. MARCH5 directly interacts with FUNDC1 to mediate its ubiquitylation at lysine 119 for subsequent degradation. Degradation of FUNDC1 by MARCH5 expression desensitizes mitochondria to hypoxia-induced mitophagy, whereas knockdown of endogenous MARCH5 significantly inhibits FUNDC1 degradation and enhances mitochondrial sensitivity toward mitophagyinducing stresses. Our findings reveal a feedback regulatory mechanism to control the protein levels of a mitochondrial receptor to fine-tune mitochondrial quality.