Inhibitors of the Thioesterase Activity of Mycobacterium tuberculosis Pks13 Discovered Using DNA-Encoded Chemical Library Screening.

DNA-encoded chemical library (DEL) technology provides a time- and cost-efficient method to simultaneously screen billions of compounds for their affinity to a protein target of interest. Here we report its use to identify a novel chemical series of inhibitors of the thioesterase activity of polyketide synthase 13 (Pks13) from Mycobacterium tuberculosis (Mtb). We present three chemically distinct series of inhibitors along with their enzymatic and Mtb whole cell potency, the measure of on-target activity in cells, and the crystal structures of inhibitor-enzyme complexes illuminating their interactions with the active site of the enzyme. One of these inhibitors showed a favorable pharmacokinetic profile and demonstrated efficacy in an acute mouse model of tuberculosis (TB) infection. These findings and assay developments will aid in the advancement of TB drug discovery.

A Small Natural Molecule S3 Protects Retinal Ganglion Cells and Promotes Parkin-Mediated Mitophagy against Excitotoxicity.

Glutamate excitotoxicity may contribute to retinal ganglion cell (RGC) degeneration in glaucoma and other optic neuropathies, leading to irreversible blindness. Growing evidence has linked impaired mitochondrial quality control with RGCs degeneration, while parkin, an E3 ubiquitin ligase, has proved to be protective and promotes mitophagy in RGCs against excitotoxicity. The purpose of this study was to explore whether a small molecule S3 could modulate parkin-mediated mitophagy and has therapeutic potential for RGCs. The results showed that as an inhibitor of deubiquitinase USP30, S3 protected cultured RGCs and improved mitochondrial health against NMDA-induced excitotoxicity. Administration of S3 promoted the parkin expression and its downstream mitophagy-related proteins in RGCs. An upregulated ubiquitination level of Mfn2 and protein level of OPA1 were also observed in S3-treated RGCs, while parkin knockdown resulted in a major loss of the protective effect of S3 on RGCs under excitotoxicity. These findings demonstrated that S3 promoted RGC survival mainly through enhancing parkin-mediated mitophagy against excitotoxicity. The neuroprotective value of S3 in glaucoma and other optic neuropathies deserves further investigation.

Benchmarking a highly selective USP30 inhibitor for enhancement of mitophagy and pexophagy.

The deubiquitylase USP30 is an actionable target considered for treatment of conditions associated with defects in the PINK1-PRKN pathway leading to mitophagy. We provide a detailed cell biological characterization of a benzosulphonamide molecule, compound 39, that has previously been reported to inhibit USP30 in an in vitro enzymatic assay. The current compound offers increased selectivity over previously described inhibitors. It enhances mitophagy and generates a signature response for USP30 inhibition after mitochondrial depolarization. This includes enhancement of TOMM20 and SYNJ2BP ubiquitylation and phosphoubiquitin accumulation, alongside increased mitophagy. In dopaminergic neurons, generated from Parkinson disease patients carrying loss of function PRKN mutations, compound 39 could significantly restore mitophagy to a level approaching control values. USP30 is located on both mitochondria and peroxisomes and has also been linked to the PINK1-independent pexophagy pathway. Using a fluorescence reporter of pexophagy expressed in U2OS cells, we observe increased pexophagy upon application of compound 39 that recapitulates the previously described effect for USP30 depletion. This provides the first pharmacological intervention with a synthetic molecule to enhance peroxisome turnover.

MF-094, a potent and selective USP30 inhibitor, accelerates diabetic wound healing by inhibiting the NLRP3 inflammasome.

Diabetes is a prevalent disease worldwide that can result in several complications, including renal failure, blindness, and amputation. Diabetic foot ulcers, which have the characteristics of chronic wounds, are a devastating component of diabetes progression that can lead to lower extremity amputation. In this study, we set out to investigate the mechanisms involved in wound healing of diabetic foot ulcers. The expression of USP30 in skin tissues of patients with diabetic foot ulcers and HSF2 human skin fibroblasts treated with advanced glycation end (AGE) products was detected by qRT-PCR, and CCK-8, cell scratch and ELISA assay were used to detect cell viability, migration and levels of Col I, Col III, MMP-2, MMP-9, IL-1ß and IL-18. The interaction between USP30 and NLRP3 was verified by co-immunoprecipitation and ubiquitination assays. The expression of USP30, NLRP3 and caspase-1 p20 was detected by Western blot. USP30 inhibitor MF-094 was used to treat diabetic rat model established by streptozotocin (STZ). We found that USP30, a deubiquitinase, was upregulated in skin tissues of patients with diabetic foot ulcers compared with normal skin tissues. In vitro, we found that treatment of HSF2 human skin fibroblasts with advanced glycation end (AGE) products, known to contribute to diabetic complications, resulted in suppressed viability and migration of HSF2 cells, as well as increased levels of USP30 mRNA and protein. Functionally, downregulation of USP30 via shRNA-mediated knockdown or treatment with the USP30 inhibitor MF-094, restored viability and migration of AGE-treated HSF2 cells. We identified the NLRP3 inflammasome as a critical target of USP30 in AGE-induced functions. Mechanistically, we demonstrate that USP30 activates the NLRP3 inflammasome by deubiquitinating NLRP3. Finally, we show that inhibition of USP30 via MF-094 treatment facilitated wound healing in diabetic rats and resulted in decreased protein levels of NLRP3 and its downstream target caspase-1 p20, thus establishing the physiological importance of the identified USP30-NLRP3 link. Together, our findings suggest a therapeutic potential for USP30 in diabetic foot ulcers.

USP11 controls R-loops by regulating senataxin proteostasis.

R-loops are by-products of transcription that must be tightly regulated to maintain genomic stability and gene expression. Here, we describe a mechanism for the regulation of the R-loop-specific helicase, senataxin (SETX), and identify the ubiquitin specific peptidase 11 (USP11) as an R-loop regulator. USP11 de-ubiquitinates SETX and its depletion increases SETX K48-ubiquitination and protein turnover. Loss of USP11 decreases SETX steady-state levels and reduces R-loop dissolution. Ageing of USP11 knockout cells restores SETX levels via compensatory transcriptional downregulation of the E3 ubiquitin ligase, KEAP1. Loss of USP11 reduces SETX enrichment at KEAP1 promoter, leading to R-loop accumulation, enrichment of the endonuclease XPF and formation of double-strand breaks. Overexpression of KEAP1 increases SETX K48-ubiquitination, promotes its degradation and R-loop accumulation. These data define a ubiquitination-dependent mechanism for SETX regulation, which is controlled by the opposing activities of USP11 and KEAP1 with broad applications for cancer and neurological disease.

Thioesterase induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin results in a futile cycle that inhibits hepatic ß-oxidation.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a persistent environmental contaminant, induces steatosis by increasing hepatic uptake of dietary and mobilized peripheral fats, inhibiting lipoprotein export, and repressing ß-oxidation. In this study, the mechanism of ß-oxidation inhibition was investigated by testing the hypothesis that TCDD dose-dependently repressed straight-chain fatty acid oxidation gene expression in mice following oral gavage every 4 days for 28 days. Untargeted metabolomic analysis revealed a dose-dependent decrease in hepatic acyl-CoA levels, while octenoyl-CoA and dicarboxylic acid levels increased. TCDD also dose-dependently repressed the hepatic gene expression associated with triacylglycerol and cholesterol ester hydrolysis, fatty acid binding proteins, fatty acid activation, and 3-ketoacyl-CoA thiolysis while inducing acyl-CoA hydrolysis. Moreover, octenoyl-CoA blocked the hydration of crotonyl-CoA suggesting short chain enoyl-CoA hydratase (ECHS1) activity was inhibited. Collectively, the integration of metabolomics and RNA-seq data suggested TCDD induced a futile cycle of fatty acid activation and acyl-CoA hydrolysis resulting in incomplete ß-oxidation, and the accumulation octenoyl-CoA levels that inhibited the activity of short chain enoyl-CoA hydratase (ECHS1).

Anticancer properties of bisaminoquinolines with modified linkers.

We have previously reported the unique features of dimeric bisaminoquinolines as anticancer agents and have identified their cellular target as PPT1, a protein palmitoyl-thioesterase. We now report a systematic study on the role of the linker in these constructs, both with respect to the distance between the heterocycles, the linker hydrophobicity and the methylation status (primary vs. secondary vs. tertiary) of the central nitrogen atom on the observed biological activity.

A new activator of esterase D decreases blood cholesterol level through ESD/JAB1/ABCA1 pathway.

Excessively high cholesterol content in the blood leads to nonalcohol fatty liver disease (NAFLD) and arteriosclerosis. Although there are increasing publications and patent applications to lower blood cholesterol with small chemical molecules, limited effective drugs can be available in clinic. It is necessary to uncover new targets and drugs to alleviate high cholesterol. Esterase D (ESD) is abundant in liver and it remains unknown about its role in cholesterol metabolism. Here we reported that small chemical molecule fluorescigenic pyrazoline derivative 5 (FPD5), a new ESD activator, could effectively reverse high blood cholesterol level and prevent fatty liver and arteriosclerosis in apoE-/- mice fed the high-fat diet. We also observed that FPD5 could reduce oxidized low density lipoprotein (oxLDL)-induced formation of foam cells. To further investigate the mechanism of FPD5 action on blood cholesterol modulation, we found that ESD trigged by FPD5 was aggregated in lysosome and interacted with Jun activation domain binding protein 1 (JAB1). ESD served as a deacetylase to remove Thr89 acetylation of JAB1 and increased its activity; thus, promoting the ATP-binding cassette transporters A1 (ABCA1) to accelerate cholesterol efflux. Our findings demonstrate that FPD5 decreases blood cholesterol level to ameliorate NAFLD and arteriosclerosis through ESD/JAB1/ABCA1 pathway, and ESD functions as a novel nonclassical deacetylase that hydrolyzes serine/threonine acetyl group. Our findings not only highlight that FPD5 may be a pioneer drug for alleviating blood cholesterol but also indicate that ESD is a potential drug target that promotes cholesterol metabolism.

Dexmedetomidine inhibits cell malignancy in osteosarcoma cells via miR-520a-3p-YOD1 interactome.

BACKGROUND: Osteosarcoma is a common malignant tumor in adolescents with a low 5-year survival rate. Dexmedetomidine (DEX) has been widely used for surgery of osteosarcoma patients. MiR-520a-3p and YOD1 expression was abnormal in osteosarcoma cells. However, whether DEX affects osteosarcoma progression via miR-520a-3p-YOD1 interactome needs to be explored. METHODS: We detected osteosarcoma cells biological behavior by CCK-8 assay, BrdU assay, cell adhesion assay, and apoptosis assay, respectively. The miR-520a-3p and YOD1 levels was explored in osteosarcoma cell lines by RT-qPCR or western blotting assay. RESULTS: In this study, we found that DEX treating osteosarcoma cells inhibited cell viability, proliferation and adhesion, while it promoted cell apoptosis. Moreover, miR-520a-3p targeting to YOD1 also functionally repressed cell malignancy in osteosarcoma cells. Notably, DEX treatment could inhibit YOD1 expression via upregulating miR-520a-3p, thereby suppressing cell malignancy in osteosarcoma. CONCLUSIONS: Our study first revealed that DEX inhibited malignancy of osteosarcoma cells via miR-520a-3p/YOD1 axis.

A STAT3 palmitoylation cycle promotes TH17 differentiation and colitis.

Cysteine palmitoylation (S-palmitoylation) is a reversible post-translational modification that is installed by the DHHC family of palmitoyltransferases and is reversed by several acyl protein thioesterases1,2. Although thousands of human proteins are known to undergo S-palmitoylation, how this modification is regulated to modulate specific biological functions is poorly understood. Here we report that the key T helper 17 (TH17) cell differentiation stimulator, STAT33,4, is subject to reversible S-palmitoylation on cysteine 108. DHHC7 palmitoylates STAT3 and promotes its membrane recruitment and phosphorylation. Acyl protein thioesterase 2 (APT2, also known as LYPLA2) depalmitoylates phosphorylated STAT3 (p-STAT3) and enables it to translocate to the nucleus. This palmitoylation-depalmitoylation cycle enhances STAT3 activation and promotes TH17 cell differentiation; perturbation of either palmitoylation or depalmitoylation negatively affects TH17 cell differentiation. Overactivation of TH17 cells is associated with several inflammatory diseases, including inflammatory bowel disease (IBD). In a mouse model, pharmacological inhibition of APT2 or knockout of Zdhhc7-which encodes DHHC7-relieves the symptoms of IBD. Our study reveals not only a potential therapeutic strategy for the treatment of IBD but also a model through which S-palmitoylation regulates cell signalling, which might be broadly applicable for understanding the signalling functions of numerous S-palmitoylation events.

Rapid Solid-Phase Construction of Serine Hydrolase Probes Results in Selective Activity-Based Probes for Acyl Protein Thioesterases-1/2.

Serine hydrolases (SHs) are a large, diverse family of enzymes that play various biomedically important roles. Their study has been substantially advanced by activity-based protein profiling, which makes use of covalent chemical probes for labeling the active site and detection by various methodologies. However, highly selective probes for individual SHs are scarce because probe synthesis usually takes place by time-consuming solution phase chemistry. We here report a general solid-phase synthesis toward SH chemical probes, which will speed up probe library synthesis. It involves the construction of a recognition element ending in a secondary amine followed by capping with different electrophiles. We illustrate the power of this approach by the discovery of selective chemical probes for the depalmitoylating enzymes APT-1/2. Overall, this study reports new methodologies to synthesize SH probes, while providing new reagents to study protein depalmitoylation.

PPT1 inhibition enhances the antitumor activity of anti-PD-1 antibody in melanoma.

New strategies are needed to enhance the efficacy of anti-programmed cell death protein antibody (anti-PD-1 Ab) in cancer. Here, we report that inhibiting palmitoyl-protein thioesterase 1 (PPT1), a target of chloroquine derivatives like hydroxychloroquine (HCQ), enhances the antitumor efficacy of anti-PD-1 Ab in melanoma. The combination resulted in tumor growth impairment and improved survival in mouse models. Genetic suppression of core autophagy genes, but not Ppt1, in cancer cells reduced priming and cytotoxic capacity of primed T cells. Exposure of antigen-primed T cells to macrophage-conditioned medium derived from macrophages treated with PPT1 inhibitors enhanced melanoma-specific killing. Genetic or chemical Ppt1 inhibition resulted in M2 to M1 phenotype switching in macrophages. The combination was associated with a reduction in myeloid-derived suppressor cells in the tumor. Ppt1 inhibition by HCQ, or DC661, induced cyclic GMP-AMP synthase/stimulator of interferon genes/TANK binding kinase 1 pathway activation and the secretion of interferon-ß in macrophages, the latter being a key component for augmented T cell-mediated cytotoxicity. Genetic Ppt1 inhibition produced similar findings. These data provide the rationale for this combination in melanoma clinical trials and further investigation in other cancers.

Knockdown of otubain 2 inhibits liver cancer cell growth by suppressing NF-κB signaling.

The deubiquitinase otubain 2 (OTUB2) has been reported to play significant roles in the tumorigenesis of several cancers, but the role of OTUB2 in liver cancer is not investigated yet. In the present study, OTUB2 was found significantly upregulated in liver cancer tumor tissues and cell lines, and elevated OTUB2 indicated as a negative index for the overall survival of liver cancer patients. At the cellular level, knockdown of OTUB2 markedly inhibited liver cancer cell growth. Our further investigations revealed that knockdown of OTUB2 significantly suppressed NF-κB-driving luciferase activity, and markedly inhibited the phosphorylation of NF-κB p65 in liver cancer cells, which indicated that OTUB2 mediated liver cancer cell growth by regulating NF-κB signaling. Additionally, we found that liver cancer cell lines harboring higher OTUB2 expression were more sensitive to NF-κB inhibitors, and overexpression of OTUB2 could significantly reduce the antitumor effects of NF-κB inhibitors in liver cancer cells. This study indicated that OTUB2 could be a promising target for the treatment of liver cancer in the future.

Methyl arachidonyl fluorophosphonate inhibits Mycobacterium tuberculosis thioesterase TesA and globally affects vancomycin susceptibility.

Phthiocerol dimycocerosates and phenolic glycolipids (PGL) are considered as major virulence elements of Mycobacterium tuberculosis, in particular because of their involvement in cell wall impermeability and drug resistance. The biosynthesis of these waxy lipids involves multiple enzymes, including thioesterase A (TesA). We observed that purified recombinant M. tuberculosis TesA is able to dimerize in the presence of palmitoyl-CoA and our 3D structure model of TesA with this acyl-CoA suggests hydrophobic interaction requirement for dimerization. Furthermore, we identified that methyl arachidonyl fluorophosphonate, which inhibits TesA by covalently modifying the catalytic serine, also displays a synergistic antimicrobial activity with vancomycin further warranting the development of TesA inhibitors as valuable antituberculous drug candidates.

Discovery of PqsE Thioesterase Inhibitors for Pseudomonas aeruginosa Using DNA-Encoded Small Molecule Library Screening.

Pseudomonas aeruginosa is a leading cause of hospital-acquired infections in the United States. PqsE, a thioesterase enzyme, is vital for virulence of P. aeruginosa, making PqsE an attractive target for inhibition. Neither the substrate nor the product of PqsE catalysis has been identified. A library of 550 million DNA-encoded drug-like small molecules was screened for those that bind to the purified PqsE protein. The structures of the bound molecules were identified by high throughput sequencing of the attached DNA barcodes. Putative PqsE binders with the strongest affinity features were examined for inhibition of PqsE thioesterase activity in vitro. The most potent inhibitors were resynthesized off DNA and examined for the ability to alter PqsE thermal melting and for PqsE thioesterase inhibition. Here, we report the synthesis, biological activity, mechanism of action, and early structure-activity relationships of a series of 2-(phenylcarbamoyl)benzoic acids that noncompetitively inhibit PqsE. A small set of analogs designed to probe initial structure-activity relationships showed increases in potency relative to the original hits, the best of which has an IC50 = 5 µM. Compound refinement is required to assess their in vivo activities as the current compounds do not accumulate in the P. aeruginosa cytosol. Our strategy validates DNA-encoded compound library screening as a rapid and effective method to identify catalytic inhibitors of the PqsE protein, and more generally, for discovering binders to bacterial proteins revealed by genetic screening to have crucial in vivo activities but whose biological functions have not been well-defined.

Targeting HIBCH to reprogram valine metabolism for the treatment of colorectal cancer.

Valine catabolism is known to be essential for cancer cells but the detailed mechanism remains unclear. This study is to explore the critical roles of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) in colorectal cancers (CRC) and to develop a new therapy returning valine metabolism homeostasis. High HIBCH expression was first confirmed to correlate with poor survival in patients with CRC, which was then linked to the increased cell growth, resistant apoptosis, and decreased autophagy in CRC cells. The functions of HIBCH in CRC were dependent on its mitochondrial localization. High HIBCH level was further demonstrated to promote the metabolism of tricarboxylic acid cycle as well as oxidative phosphorylation in CRC cells. Based on above findings, we further discovered a novel valine catabolism inhibitor SBF-1. The pharmacological blockade of HIBCH mitochondrial localization with SBF-1 resulted in decreased cancer cell growth and increased autophagy, collectively contributing to the antitumor effect both in vitro and in vivo. Moreover, anti-VEGF therapy with bevacizumab increased HIBCH level in CRC cells, which in turn caused the resistance to the therapy. The interference with HIBCH function by SBF-1 significantly increased the antitumor efficacy of bevacizumab and led to a robust survival benefit. The present study identified HIBCH as a critical enzyme of valine catabolism in CRC progression and resistance to anti-VEGF therapy. We also provided a novel HIBCH inhibitor SBF-1, which highlighted the combined therapy using valine catabolic inhibitor along with anti-VEGF drugs, to control progression of CRC.

An Inhibitor of Fatty Acid Synthase Thioesterase Domain with Improved Cytotoxicity against Breast Cancer Cells and Stability in Plasma.

It is well recognized that many cancers are addicted to a constant supply of fatty acids (FAs) and exhibit brisk de novo FA synthesis. Upregulation of a key lipogenic enzyme, fatty acid synthase (FASN), is a near-universal feature of human cancers and their precursor lesions, and has been associated with chemoresistance, tumor metastasis, and diminished patient survival. FASN inhibition has been shown to be effective in killing cancer cells, but progress in the field has been hindered by off-target effects and poor pharmaceutical properties of candidate compounds. Our initial hit (compound 1) was identified from a high-throughput screening effort by the Sanford-Burnham Center for Chemical Genomics using purified FASN thioesterase (FASN-TE) domain. Despite being a potent inhibitor of purified FASN-TE, compound 1 proved highly unstable in mouse plasma and only weakly cytotoxic to breast cancer (BC) cells in vitro. An iterative process of synthesis, cytotoxicity testing, and plasma stability assessment was used to identify a new lead (compound 41). This lead is more cytotoxic against multiple BC cell lines than tetrahydro-4-methylene-2S-octyl-5-oxo-3R-furancarboxylic acid (the literature standard for inhibiting FASN), is stable in mouse plasma, and shows negligible cytotoxic effects against nontumorigenic mammary epithelial cells. Compound 41 also has drug-like physical properties based on Lipinski's rules and is, therefore, a valuable new lead for targeting fatty acid synthesis to exploit the requirement of tumor cells for fatty acids. SIGNIFICANCE STATEMENT: An iterative process of synthesis and biological testing was used to identify a novel thioesterase domain FASN inhibitor that has drug-like properties, is more cytotoxic to breast cancer cells than the widely used tetrahydro-4-methylene-2S-octyl-5-oxo-3R-furancarboxylic acid, and has negligible effects on the growth and proliferation of noncancerous mammary epithelial cells. Our studies have confirmed the value of using potent and selective FASN inhibitors in the treatment of BC cells and have shown that the availability of exogenous lipoproteins may impact both cancer cell FA metabolism and survival.

CRISPR/Cas9 mediated generation of an ovine model for infantile neuronal ceroid lipofuscinosis (CLN1 disease).

The neuronal ceroid lipofuscinoses (NCLs) are a group of devastating monogenetic lysosomal disorders that affect children and young adults with no cure or effective treatment currently available. One of the more severe infantile forms of the disease (INCL or CLN1 disease) is due to mutations in the palmitoyl-protein thioesterase 1 (PPT1) gene and severely reduces the child's lifespan to approximately 9 years of age. In order to better translate the human condition than is possible in mice, we sought to produce a large animal model employing CRISPR/Cas9 gene editing technology. Three PPT1 homozygote sheep were generated by insertion of a disease-causing PPT1 (R151X) human mutation into the orthologous sheep locus. This resulted in a morphological, anatomical and biochemical disease phenotype that closely resembles the human condition. The homozygous sheep were found to have significantly reduced PPT1 enzyme activity and accumulate autofluorescent storage material, as is observed in CLN1 patients. Clinical signs included pronounced behavioral deficits as well as motor deficits and complete loss of vision, with a reduced lifespan of 17 ± 1 months at a humanely defined terminal endpoint. Magnetic resonance imaging (MRI) confirmed a significant decrease in motor cortical volume as well as increased ventricular volume corresponding with observed brain atrophy and a profound reduction in brain mass of 30% at necropsy, similar to alterations observed in human patients. In summary, we have generated the first CRISPR/Cas9 gene edited NCL model. This novel sheep model of CLN1 disease develops biochemical, gross morphological and in vivo brain alterations confirming the efficacy of the targeted modification and potential relevance to the human condition.

gga-miRNA-18b-3p Inhibits Intramuscular Adipocytes Differentiation in Chicken by Targeting the ACOT13 Gene.

Intramuscular fat (IMF) is the most important evaluating indicator of chicken meat quality, the content of which is positively correlated with tenderness, flavor, and succulence of the meat. Chicken IMF deposition process is regulated by many factors, including genetic, nutrition, and environment. Although large number of omics' studies focused on the IMF deposition process, the molecular mechanism of chicken IMF deposition is still poorly understood. In order to study the role of miRNAs in chicken intramuscular adipogenesis, the intramuscular adipocyte differentiation model (IMF-preadipocytes and IMF-adipocytes) was established and subject to miRNA-Seq. A total of 117 differentially expressed miRNAs between two groups were obtained. Target genes prediction and functional enrichment analysis revealed that eight pathways involved in lipid metabolism related processes, such as fatty acid metabolism and fatty acid elongation. Meanwhile a putative miRNA, gga-miR-18b-3p, was identified be served a function in the intramuscular adipocyte differentiation. Luciferase assay suggested that the gga-miR-18b-3p targeted to the 3'UTR of ACOT13. Subsequent functional experiments demonstrated that gga-miR-18b-3p acted as an inhibitor of intramuscular adipocyte differentiation by targeting ACOT13. Our findings laid a new theoretical foundation for the study of lipid metabolism, and also provided a potential target to improve the meat quality in the poultry industry.

Therapeutic approaches to enhance PINK1/Parkin mediated mitophagy for the treatment of Parkinson's disease.

The discovery of rare familial monogenic forms of early-onset Parkinson's disease has led to the identification of a mitochondrial quality control process as a key player in this disease. Loss-of-function mutations in the genes encoding PINK1 or Parkin result in insufficient removal of dysfunctional mitochondria through autophagy, a process termed mitophagy. Understanding the mechanism of this process and the function of its two key players, PINK1 and Parkin, has led to the discovery of new therapeutic approaches. Small molecule activators of mitophagy, either activating PINK1 or Parkin directly or inhibiting Parkin's counterplayer, the ubiquitin-specific protease USP30, are in preclinical development. To enable clinical success of future small molecule mitophagy enhancers, biomarkers for mitochondrial integrity and mitophagy are being developed. Only a few years after the discovery of mitophagy deficits in Parkinson's disease, research of the underlying mechanisms, drug discovery of modulators for this mechanism and identification of biomarkers provide new avenues towards the development of disease-modifying therapies.