Fatty acids are the most efficient substrates for energy production in vertebrates and are essential components of the lipids that form biological membranes. Synthesis of triacylglycerols from non-esterified free fatty acids (FFAs) combined with triacylglycerol storage represents a highly efficient strategy to stockpile FFAs in cells and prevent FFA-induced lipotoxicity. Although essentially all vertebrate cells have some capacity to store and utilize triacylglycerols, white adipose tissue is by far the largest triacylglycerol depot and is uniquely able to supply FFAs to other tissues. The release of FFAs from triacylglycerols requires their enzymatic hydrolysis by a process called lipolysis. Recent discoveries thoroughly altered and extended our understanding of lipolysis. This Review discusses how cytosolic 'neutral' lipolysis and lipophagy, which utilizes 'acid' lipolysis in lysosomes, degrade cellular triacylglycerols as well as how these pathways communicate, how they affect lipid metabolism and energy homeostasis and how their dysfunction affects the pathogenesis of metabolic diseases. Answers to these questions will likely uncover novel strategies for the treatment of prevalent metabolic diseases.

Cytosolic lipolysis and lipophagy: two sides of the same coin

A GGGGCC hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). C9orf72 encodes two C9orf72 protein isoforms of unclear function. Reduced levels of C9orf72 expression have been reported in C9ALS/FTD patients, and although C9orf72 haploinsufficiency has been proposed to contribute to C9ALS/FTD, its significance is not yet clear. Here, we report that C9orf72 interacts with Rab1a and the Unc-51-like kinase 1 (ULK1) autophagy initiation complex. As a Rab1a effector, C9orf72 controls initiation of autophagy by regulating the Rab1a-dependent trafficking of the ULK1 autophagy initiation complex to the phagophore. Accordingly, reduction of C9orf72 expression in cell lines and primary neurons attenuated autophagy and caused accumulation of p62-positive puncta reminiscent of the p62 pathology observed in C9ALS/FTD patients. Finally, basal levels of autophagy were markedly reduced in C9ALS/FTD patient-derived iNeurons. Thus, our data identify C9orf72 as a novel Rab1a effector in the regulation of autophagy and indicate that C9orf72 haploinsufficiency and associated reductions in autophagy might be the underlying cause of C9ALS/FTD-associated p62 pathology.

https://www.embopress.org/doi/pdf/10.15252/embj.201694401

The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy.

Defective autophagy contributes to Alzheimer disease (AD) pathogenesis although evidence is conflicting on whether multiple stages are impaired. Here, for the first time, we have comprehensively evaluated the entire autophagic process specifically in CA1 pyramidal neurons of hippocampus from early and late-stage AD subjects and nondemented controls. CA1 neurons aspirated by laser capture microdissection were analyzed using a custom-designed microarray comprising 578 neuropathology- and neuroscience-associated genes. Striking upregulation of autophagy-related genes, exceeding that of other gene ontology groups, reflected increases in autophagosome formation and lysosomal biogenesis beginning at early AD stages. Upregulated autophagosome formation was further indicated by elevated gene and protein expression levels for autophagosome components and increased LC3-positive puncta. Increased lysosomal biogenesis was evidenced by activation of MiTF/TFE family transcriptional regulators, particularly TFE3 (transcription factor binding to IGHM enhancer 3) and by elevated expression of their target genes and encoded proteins. Notably, TFEB (transcription factor EB) activation was associated more strongly with glia than neurons. These findings establish that autophagic sequestration is both competent and upregulated in AD. Autophagosome-lysosome fusion is not evidently altered. Despite this early disease response, however, autophagy flux is progressively impeded due to deficient substrate clearance, as reflected by autolysosomal accumulation of LC3-II and SQSTM1/p62 and expansion of autolysosomal size and total area. We propose that sustained induction of autophagy in the face of progressively declining lysosomal clearance of substrates explains the uncommonly robust autophagic pathology and neuritic dystrophy implicated in AD pathogenesis.

https://tandfonline.com/doi/pdf/10.1080/15548627.2016.1239003

Autophagy flux in CA1 neurons of Alzheimer hippocampus: Increased induction overburdens failing lysosomes to propel neuritic dystrophy.

Cellular and metabolic functions for autophagy in cancer cells

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.27667

The small GTPase Rab7 as a central regulator of hepatocellular lipophagy.

Autophagy (macroautophagy) is a highly conserved intracellular and lysosome-dependent degradation process in which autophagic substrates are enclosed and degraded by a double-membrane vesicular structure in a continuous and dynamic vesicle transport process. The Rab protein is a small GTPase that belongs to the Ras-like GTPase superfamily and regulates the vesicle traffic process. Numerous Rab proteins have been shown to be involved in various stages of autophagy. Rab1, Rab5, Rab7, Rab9A, Rab11, Rab23, Rab32, and Rab33B participate in autophagosome formation, whereas Rab9 is required in non-canonical autophagy. Rab7, Rab8B, and Rab24 have a key role in autophagosome maturation. Rab8A and Rab25 are also involved in autophagy, but their role is unknown. Here, we summarize new findings regarding the involvement of Rabs in autophagy and provide insights regarding future research on the mechanisms of autophagy regulation.

/pdf/regulation-of-autophagy-by-the-rab-gtpase-network-42dvqxkzu3.pdf

Regulation of autophagy by the Rab GTPase network

Two groups of ceria nanoparticles with similar size but different crystallinity were synthesized.The crystallinity of the nanoparticles, as a critical parameter, was negatively correlated with their SOD-like activity, because nanoparticles with lower crystallinity had a higher proportion of Ce3+/Ce4+. The nanoparticles featuring lower crystallinity could better protect MSCs from oxidative stress. 

Decreasing crystallinity is beneficial to the superoxide dismutase like activity of ceria nanoparticles

Ceria nanoparticles (CNPs) is an important typical nanozyme with multiple enzyme mimetic activities, which could facilitate the oxidation of organic dyes in acidic conditions, because of the oxidase mimetic activity. Usually, the regulation of oxidase mimetic activity is focused on the adjustment of the structure, morphology, composition, surface, and other factors of nanozymes. However, the influence of the surrounding environment is not considered, which is very important during the reaction process. In this work, the oxidase mimetic activity of CNPs in buffer solutions including citric acid, acetic acid and glycine buffer solutions was investigated, with the results that carboxyl group in buffer solution could adsorb the CNPs on the surface to promote the oxidase mimetic activity. Due to the chelation with cerium ion, the enhancement is more significant by molecules with polycarboxylic groups, and the enhancement is more efficient by carboxyl molecules in buffer solution, compared with the modification of the carboxyl groups on the surface, because of the easier operation and smaller steric hindrance. From viewpoint of increasing the oxidase mimetic activity of CNPs, the work is expected to provide references for the selection of the reaction system to optimize the oxidase mimetic activity in bio-detection application.

Regulation of the oxidase mimetic activity of ceria nanoparticles by buffer composition.

The overproduction of reactive oxygen species (ROS) is one of the major reasons for the aggravation of acute lung injury (ALI). Smaller‐sized ceria nanoparticles featured with higher ROS scavenging capability than their bigger‐sized counterparts are potential candidates for ALI therapy. However, smaller‐sized ceria nanoparticles are more easily accumulated in spleen and liver rather than lung. Herein, it is reported that this obstacle can be addressed by constructing ceria into ultrafine nanowires, through which the ultrafine diameter ensures the high ROS scavenging activity and the high aspect ratio promotes the lung targeted accumulation. To demonstrate the feasibility of this conception, a platform is developed to realize length‐controlled ceria nanowires (diameter of ≈1.5 nm) synthesis. These nanowires are PEGylated using a carefully optimized procedure that can preserve their fragile crystal structures. The PEGylated nanowires exhibit higher ROS scavenging capabilities than the ≈3.9 nm sized nanoparticles. Most importantly, lung targeted accumulation can be realized through modulating the length of the nanowires, where the longer nanowires (>100 nm) show much higher lung accumulation. Due to these properties, the longer ceria nanowires can effectively scavenge the overproduced ROS during the progression of ALI, and thereby inhibit the edema and inflammation in the lung tissue.

Length‐Controlled Construction of Ceria Nanowires with Ultrafine Diameter and Stable Morphology for Targeted Acute Lung Injury Therapy

• Crystal structure optimized MCNs can degrade 90% organic dye in 3 minutes. • The MCNs are highly active in wide range of H 2 O 2 concentrations and pH values. • The excellent activity of MCNs is mainly due to the fast adsorption equilibrium rate. Photo-Fenton reactions are quite promising in industrial pollutants degradation by virtue of their high efficiency, low cost and easy operation properties. Ceria is one category of the most versatile inorganic catalysts based on its semiconductor nature and fast Ce 3+ /Ce 4+ exchange capability in the crystal. Recently, ceria has been explored as Photo-Fenton reaction catalysts for pollutants degradation. However, the sharp decrease of catalytic activity in neutral or alkaline solution is in the way of its further practical application. In this study, four mesoporous ceria nanoparticles (MCNs) featured with slight difference of structure parameters were synthesized and their feasibility in catalyzing Photo-Fenton reactions were evaluated. The crystal structure optimized MCNs-240 could realize over 90% dye degradation ratio within 3 minutes, which was much more efficient than the previously reported ceria catalysts. Meanwhile, the change of reaction conditions including the H 2 O 2 concentration (5 to 80 mM) and pH value (2.5 to 8.5) had minimal effects on its catalytic activity. These results implied that the MCNs-240 was an excellent candidate for catalyzing ultra-fast and highly flexible Photo-Fenton reaction. The revealed mechanisms indicated that the fast dye adsorption equilibrium rate and decreased bandgap were the main reasons for the outstanding catalytic performance of the MCNs-240. 

L Zou

Papers

Regulation of autophagy by the Rab GTPase network

Decreasing crystallinity is beneficial to the superoxide dismutase like activity of ceria nanoparticles

Regulation of the oxidase mimetic activity of ceria nanoparticles by buffer composition.

Length‐Controlled Construction of Ceria Nanowires with Ultrafine Diameter and Stable Morphology for Targeted Acute Lung Injury Therapy

Mesoporous ceria nanoparticles for ultra-fast and highly flexible photo-Fenton catalytic reaction