Fatty acids are essential for survival, acting as bioenergetic substrates, structural components and signalling molecules. Given their vital role, cells have evolved mechanisms to generate fatty acids from alternative carbon sources, through a process known as de novo lipogenesis (DNL). Despite the importance of DNL, aberrant upregulation is associated with a wide variety of pathologies. Inhibiting core enzymes of DNL, including citrate/isocitrate carrier (CIC), ATP-citrate lyase (ACLY), acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), represents an attractive therapeutic strategy. Despite challenges related to efficacy, selectivity and safety, several new classes of synthetic DNL inhibitors have entered clinical-stage development and may become the foundation for a new class of therapeutics. De novo lipogenesis (DNL) is vital for the maintenance of whole-body and cellular homeostasis, but aberrant upregulation of the pathway is associated with a broad range of conditions, including cardiovascular disease, metabolic disorders and cancers. Here, Steinberg and colleagues provide an overview of the physiological and pathological roles of the core DNL enzymes and assess strategies and agents currently in development to therapeutically target them. 

/pdf/lipogenesis-inhibitors-therapeutic-opportunities-and-1g9yc80s.pdf

Lipogenesis inhibitors: therapeutic opportunities and challenges

Pancreatic ductal adenocarcinoma (PDAC), the fourth leading cause of cancer death, has a 5-year survival rate of approximately 7-9%. The ineffectiveness of anti-PDAC therapies is believed to be due to the existence of a subpopulation of tumor cells known as cancer stem cells (CSCs), which are functionally plastic, and have exclusive tumorigenic, chemoresistant and metastatic capacities. Herein, we describe a 2D in vitro system for long-term enrichment of pancreatic CSCs that is amenable to biological and CSC-specific studies. By changing the carbon source from glucose to galactose in vitro, we force PDAC cells to utilize OXPHOS, resulting in enrichment of CSCs defined by increased CSC biomarker and pluripotency gene expression, greater tumorigenic potential, induced but reversible quiescence, increased OXPHOS activity, enhanced invasiveness, and upregulated immune evasion properties. This CSC enrichment method can facilitate the discovery of new CSC-specific hallmarks for future development into targets for PDAC-based therapies.

/pdf/exploiting-oxidative-phosphorylation-to-promote-the-stem-and-3xw17bai6b.pdf

Exploiting oxidative phosphorylation to promote the stem and immunoevasive properties of pancreatic cancer stem cells

Bone marrow-derived mesenchymal stem cell (BMSC) transplantation is considered a promising therapeutic approach for bone defect repair However, during the transplantation procedure, the functions and viability of BMSCs may be impaired due to extended durations of in vitro culture, aging, and disease conditions of patients Inspired by spontaneous intercellular mitochondria transfer that naturally occurs within injured tissues to rescue cellular or tissue function, we investigated whether artificial mitochondria transfer into pre-transplant BMSCs in vitro could improve cellular function and enhance their therapeutic effects on bone defect repair in situ Mitochondria were isolated from donor BMSCs and transferred into recipient BMSCs of the same batch and passage Subsequently, changes in proliferative capacity and cell senescence were evaluated by live cell imaging, Cell Counting Kit-8 assay, cell cycle analysis, Ki67 staining, qPCR and Western blot analysis of c-Myc expression, and β-galactosidase staining Migration ability was evaluated by the transwell migration assay, wound scratch healing, and cell motility tests Alkaline phosphatase (ALP) staining, Alizarin Red staining, and combined with qPCR and Western blot analyses of Runx2 and BMP2 were performed to elucidate the effects of mitochondria transfer on the osteogenic potential of BMSCs in vitro After that, in vivo experiments were performed by transplanting mitochondria-recipient BMSCs into a rat cranial critical-size bone defect model Micro CT scanning and histological analysis were conducted at 4 and 8 weeks after transplantation to evaluate osteogenesis in situ Finally, in order to establish the correlation between cellular behavioral changes and aerobic metabolism, OXPHOS (oxidative phosphorylation) and ATP production were assessed and inhibition of aerobic respiration by oligomycin was performed Mitochondria-recipient BMSCs exhibited significantly enhanced proliferation and migration, and increased osteogenesis upon osteogenic induction The in vivo results showed more new bone formation after transplantation of mitochondria-recipient BMSCs in situ Increased OXPHOS activity and ATP production were observed, which upon inhibition by oligomycin attenuated the enhancement of proliferation, migration, and osteogenic differentiation induced by mitochondria transfer Mitochondria transfer is a feasible technique to enhance BMSC function in vitro and promote bone defect repair in situ through the upregulation of aerobic metabolism The results indicated that mitochondria transfer may be a novel promising technique for optimizing stem cell therapeutic function

/pdf/mitochondria-transfer-enhances-proliferation-migration-and-1hl4ab8flz.pdf

Mitochondria transfer enhances proliferation, migration, and osteogenic differentiation of bone marrow mesenchymal stem cell and promotes bone defect healing

Mesenchymal stem cells (MSCs) are multipotent cells that show self-renewal, multi-directional differentiation, and paracrine and immune regulation. As a result of these properties, the MSCs have great clinical application prospects, especially in the regeneration of injured tissues, functional reconstruction, and cell therapy. However, the transplanted MSCs are prone to ageing and apoptosis and have a difficult to control direction differentiation. Therefore, it is necessary to effectively regulate the functions of the MSCs to promote their desired effects. In recent years, it has been found that mitochondria, the main organelles responsible for energy metabolism and adenosine triphosphate production in cells, play a key role in regulating different functions of the MSCs through various mechanisms. Thus, mitochondria could act as effective targets for regulating and promoting the functions of the MSCs. In this review, we discuss the research status and current understanding of the role and mechanism of mitochondrial energy metabolism, morphology, transfer modes, and dynamics on MSC functions.

/pdf/the-role-and-mechanism-of-mitochondrial-functions-and-energy-35hrjum5vp.pdf

The role and mechanism of mitochondrial functions and energy metabolism in the function regulation of the mesenchymal stem cells.

The skeleton is diverse in its functions, which include mechanical support, movement, blood cell production, mineral storage and endocrine regulation. This multifaceted role is achieved through an interplay of osteoblasts, chondrocytes, bone marrow adipocytes and stromal cells, all generated from skeletal stem cells. Emerging evidence shows the importance of cellular metabolism in the molecular control of the skeletal system. The different skeletal cell types not only have distinct metabolic demands relating to their particular functions but also are affected by microenvironmental constraints. Specific metabolites control skeletal stem cell maintenance, direct lineage allocation and mediate cellular communication. Here, we discuss recent findings on the roles of cellular metabolism in determining skeletal stem cell fate, coordinating osteoblast and chondrocyte function, and organizing stromal support of haematopoiesis. We also consider metabolic dysregulation in skeletal ageing and degenerative diseases, and provide an outlook on how the field may evolve in the coming years. Van Gastel and Carmeliet provide an overview of emerging findings on how cellular metabolism shapes skeletal stem cell fate and function, and discuss how metabolic dysregulation might contribute to skeletal ageing and degenerative diseases.

Metabolic regulation of skeletal cell fate and function in physiology and disease.

Active mitochondria support osteogenic differentiation by stimulating β-catenin acetylation

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Active mitochondria support osteogenic differentiation by stimulating β-catenin acetylation