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Ana C Bento, Claudia C Bippes, Corina Kohler, Charles Hemion, Stephan Frank, Albert Neutzner
Clearance of damaged mitochondria through mitophagy is critical for maintaining mitochondrial fidelity and the prevention of neurodegeneration. Here, we report on the UBX domain-containing, p97/VCP cofactor UBXD1/UBXN6/UBXDC2 and its role in mitophagy. Recognizing depolarized mitochondria via its C-terminal UBX domain, UBXD1 translocates to mitochondria in a Parkin-dependent manner. During Parkin-independent mitophagy, UBXD1 shows no mitochondrial translocation. Once translocated, UBXD1 recruits p97 to mitochondria via a bipartite binding motif consisting of its N-terminal VIM and PUB domains...
August 17, 2018: Scientific Reports
Ching-Chi Chiu, Chin-Song Lu, Yi-Hsin Weng, Ying-Ling Chen, Ying-Zu Huang, Rou-Shayn Chen, Yi-Chuan Cheng, Yin-Cheng Huang, Yu-Chuan Liu, Szu-Chia Lai, Kun-Jun Lin, Yan-Wei Lin, Yu-Jie Chen, Chao-Lang Chen, Tu-Hsueh Yeh, Hung-Li Wang
PARK14 patients with homozygous (D331Y) PLA2G6 mutation display motor deficits of pure early-onset Parkinson's disease (PD). The aim of this study is to investigate the pathogenic mechanism of mutant (D331Y) PLA2G6-induced PD. We generated knockin (KI) mouse model of PARK14 harboring homozygous (D331Y) PLA2G6 mutation. Then, we investigated neuropathological and neurological phenotypes of PLA2G6D331Y/D331Y KI mice and molecular pathogenic mechanisms of (D331Y) PLA2G6-induced degeneration of substantia nigra (SN) dopaminergic neurons...
August 8, 2018: Molecular Neurobiology
Alex Von Schulze, Colin S McCoin, Chiemela Onyekere, Julie Allen, Paige Geiger, Gerald W Dorn, E Matthew Morris, John P Thyfault
KEY POINTS SUMMARY: Hepatic mitochondrial adaptations to physical activity may be regulated by mitochondrial biogenesis (PGC1α) and mitophagy (BNIP3). Additionally, these adaptations may be sex-dependent. Chronic increases in physical activity lowers basal mitochondrial respiratory capacity in mice. Female mice have higher hepatic ETS protein content, elevated respiratory capacity, lowered mitophagic flux, and emit less mitochondrial H2 O2 independent of physical activity. Males require chronic daily physical activity to attain a similar mitochondrial phenotype compared to females...
July 31, 2018: Journal of Physiology
Wenhui Li, Yanjun Li, Sami Siraj, Haojie Jin, Yuyuan Fan, Xinrong Yang, Xiaowu Huang, Xiaohui Wang, Jun Wang, Lei Liu, Lei Du, Quan Chen
Mitochondria lie at the heart of innate immunity, and aberrant mitochondrial activity contributes to immune activation and chronic inflammatory diseases including liver cancers. Mitophagy is a selective process for removing dysfunctional mitochondria. The link between mitophagy and inflammation in tumorigenesis remains largely unexplored. We observed that FUNDC1, a previously characterized mitophagy receptor, accumulates in most human hepatocellular carcinomas (HCCs), and we thus explored the role of FUNDC1-mediated mitophagy in HCC initiation and progression in a mouse model in which HCC is induced by the chemical carcinogen diethylnitrosamine (DEN)...
July 27, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Zachary Graham, Lauren Harlow, William A Bauman, Christopher P Cardozo
INTRODUCTION: Paralysis and unloading of skeletal muscle leads to a rapid loss in muscle size, function and oxidative capacity. The reduction in metabolic capability after disuse leads to dysregulation and increased breakdown of mitochondria by mitophagy. METHODS: Eight-week old C57BL/6 male mice were given a sham surgery or sciatic nerve transection. Animals were sacrificed at 7, 14, 21 or 35 d post-surgery. Whole gastrocnemius muscles were isolated from the animal, weighed and used for Western blotting...
July 20, 2018: Muscle & Nerve
Nina Meyer, Svenja Zielke, Jonas B Michaelis, Benedikt Linder, Verena Warnsmann, Stefanie Rakel, Heinz D Osiewacz, Simone Fulda, Michel Mittelbronn, Christian Münch, Christian Behrends, Donat Kögel
In most cases, macroautophagy/autophagy serves to alleviate cellular stress and acts in a pro-survival manner. However, the effects of autophagy are highly contextual, and autophagic cell death (ACD) is emerging as an alternative paradigm of (stress- and drug-induced) cell demise. AT 101 ([-]-gossypol), a natural compound from cotton seeds, induces ACD in glioma cells as confirmed here by CRISPR/Cas9 knockout of ATG5 that partially, but significantly rescued cell survival following AT 101 treatment. Global proteomic analysis of AT 101-treated U87MG and U343 glioma cells revealed a robust decrease in mitochondrial protein clusters, whereas HMOX1 (heme oxygenase 1) was strongly upregulated...
July 21, 2018: Autophagy
Britney N Lizama, Amy M Palubinsky, Vineeth A Raveendran, Annah M Moore, Joel D Federspiel, Simona G Codreanu, Daniel C Liebler, BethAnn McLaughlin
C-terminus of HSC70-interacting protein (CHIP, STUB1 ) is a ubiquitously expressed cytosolic E3-ubiquitin ligase. CHIP-deficient mice exhibit cardiovascular stress and motor dysfunction prior to premature death. This phenotype is more consistent with animal models in which master regulators of autophagy are affected rather than with the mild phenotype of classic E3-ubiquitin ligase mutants. The cellular and biochemical events that contribute to neurodegeneration and premature aging in CHIP KO models remain poorly understood...
June 22, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Thomas Neill, Eva Andreuzzi, Zi-Xuan Wang, Stephen C Peiper, Maurizo Mongiat, Renato V Iozzo
Regulation of autophagy by proteolytically-cleaved fragments of heparan sulfate proteoglycans is a novel and current research focus in tumor biology. Endorepellin, is the C-terminal angiostatic fragment of the heparan sulfate proteoglycan perlecan and, induces autophagy in endothelial cells. To further investigate this property, we used NanoString, a digital PCR platform for measuring pre-defined transcripts in biological samples to analyze a custom subset of 95 autophagy-related genes in human umbilical vein endothelial cells treated with ultrapure human recombinant endorepellin...
June 19, 2018: Journal of Biological Chemistry
Linliang Zhang, Yali Qin, Mingzhou Chen
Viral infection causes many physiological alterations in the host cell, and many of these alterations can affect the host mitochondrial network, including mitophagy induction. A substantial amount of literature has been generated that advances our understanding of the relationship between mitophagy and several viruses. Some viruses trigger mitophagy directly, and indirectly and control the mitophagic process via different strategies. This enables viruses to promote persistent infection and attenuate the innate immune responses...
June 12, 2018: Autophagy
Huang Deyu, Cui Luqing, Liu Xianglian, Guo Pu, Lu Qirong, Wang Xu, Yuan Zonghui
T-2 toxin is the most toxic member of trichothecene mycotoxin. So far, the mechanism of mitochondrial toxicity and protective mechanism in mammalian cells against T-2 toxin are not fully understood. In this study, we aimed to investigate the cellular and mitochondrial toxicity of T-2 toxin, and the cellular protective mechanisms in rat pituitary GH3 cells. We showed that T-2 toxin significantly increased reactive oxygen species (ROS) and DNA damage and caused apoptosis in GH3 cells. T-2 toxin induced abnormal cell morphology, cytoplasm and nuclear shrinkage, nuclear fragmentation and formation of apoptotic bodies and autophagosomes...
June 2, 2018: Toxicology Letters
Chris Chin Wah Chen, Avigail T Erlich, Matthew J Crilly, David A Hood
The maintenance of muscle health with advancing age is dependent on mitochondrial homeostasis. While reductions in mitochondrial biogenesis have been observed with age, less is known regarding organelle degradation. Parkin is an E3 ubiquitin ligase implicated in mitophagy, but few studies have examined Parkin's contribution to mitochondrial turnover in muscle. Wild type (WT) and Parkin knockout (KO) mice were used to delineate a role for Parkin-mediated mitochondrial degradation in aged muscle, in concurrence with exercise...
May 29, 2018: American Journal of Physiology. Endocrinology and Metabolism
Frédéric Checler, Thomas Goiran, Cristine Alves da Costa
The tumor suppressor TP53/p53 is a key protein in both neurodegenerative diseases and cancer. Thus, TP53-linked cell death appears exacerbated in several age-related neuropathologies, while TP53 mutation-associated phenotypes indicate a loss of function accounting for approximately half of cancers. Thus, TP53 plays a pivotal role in these phenotypically distinct pathologies, a hypothesis reinforced by recent epidemiological studies suggesting an opposite risk to develop one type of pathology relative to the other...
May 11, 2018: Autophagy
Nan Li, Hengjin Wang, Chunming Jiang, Miao Zhang
Autophagy is upregulated under stress conditions to degrade superfluous proteins and recycle damaged organelles including damaged mitochondria. However, the occurrence of mitochondrial autophagy and its contribution remain to be elucidated during renal ischemia/reperfusion injury (IRI). In this study, mitophagosomes and engulfed mitochondria were frequently observed by electron microscopy after renal IRI vs. control. Meanwhile, the increase of lipidated microtubule associated protein light chain 3 (LC3-II) and decrease of mitochondrial proteins were detected by western blot, suggesting the presence of mitophagy...
August 1, 2018: Experimental Cell Research
Xueyan Gu, Yongmei Qi, Zengxiu Feng, Lin Ma, Ke Gao, Yingmei Zhang
Lead (Pb), a widely distributed environmental pollutant, is known to induce mitochondrial damage as well as autophagy in vitro and in vivo. In this study, we found that Pb could trigger mitophagy in both HEK293 cells and the kidney cortex of male Kunming mice. However, whether ataxia telangiectasis mutated (ATM) which is reported to be linked with PTEN-induced putative kinase 1 (PINK1)/Parkin pathway (a well-characterized mitophagic pathway) participates in the regulation of Pb-induced mitophagy and its exact role remains enigmatic...
July 2018: Toxicology Letters
Marcos Lahuerta, Carmen Aguado, Pablo Sánchez-Martín, Pascual Sanz, Erwin Knecht
Lafora disease (LD) is a fatal neurodegenerative disorder caused mostly by mutations in either of two genes encoding laforin and malin. LD is characterized by accumulation of a poorly branched form of glycogen in the cytoplasm of neurons and other cells. We previously reported dysfunctional mitochondria in different LD models. Now, using mitochondrial uncouplers and respiratory chain inhibitors, we have investigated with human fibroblasts a possible alteration in the selective degradation of damaged mitochondria (mitophagy) in LD...
June 2018: FEBS Journal
Jeong-Min Hong, Sun-Mee Lee
AIMS: Heme oxygenase-1 (HO-1), an endogenous cytoprotective enzyme, is reported that can be localized in mitochondria under stress, contributing to preserve mitochondrial function. Mitochondrial quality control (QC) is essential to cellular health and recovery linked with redox homeostasis. Recent studies reported that phosphoglycerate mutase family member (PGAM) 5, a mitochondria-resident phosphatase, plays critical role in mitochondrial homeostasis. Therefore, we aim to investigate cytoprotective mechanisms of HO-1 in I/R-induced hepatic injury focusing on mitochondrial QC associated with PGAM5 signaling...
May 1, 2018: Life Sciences
Diego Grassi, Shannon Howard, Minghai Zhou, Natalia Diaz-Perez, Nicolai T Urban, Debbie Guerrero-Given, Naomi Kamasawa, Laura A Volpicelli-Daley, Philip LoGrasso, Corinne Ida Lasmézas
Exposure of cultured primary neurons to preformed α-synuclein fibrils (PFFs) leads to the recruitment of endogenous α-synuclein and its templated conversion into fibrillar phosphorylated α-synuclein (pα-synF) aggregates resembling those involved in Parkinson's disease (PD) pathogenesis. Pα-synF was described previously as inclusions morphologically similar to Lewy bodies and Lewy neurites in PD patients. We discovered the existence of a conformationally distinct, nonfibrillar, phosphorylated α-syn species that we named "pα-syn*...
March 13, 2018: Proceedings of the National Academy of Sciences of the United States of America
Alba Timón-Gómez, David Sanfeliu-Redondo, Amparo Pascual-Ahuir, Markus Proft
Repair and removal of damaged mitochondria is a key process for eukaryotic cell homeostasis. Here we investigate in the yeast model how different protein complexes of the mitochondrial electron transport chain are subject to specific degradation upon high respiration load and organelle damage. We find that the turnover of subunits of the electron transport complex I equivalent and complex III is preferentially stimulated upon high respiration rates. Particular mitochondrial proteases, but not mitophagy, are involved in this activated degradation...
2018: Frontiers in Microbiology
Katja Weckmann, Philip Diefenthäler, Marius W Baeken, Kamran Yusifli, Christoph W Turck, John M Asara, Christian Behl, Parvana Hajieva
The ability of cells to rearrange their metabolism plays an important role in compensating the energy shortage and may provide cell survival. Our study focuses on identifing the important adaptational changes under the conditions of oxygen and glucose reduction. Employing mass spectrometry-based metabolomics in combination with biochemistry and microscopy techniques we identified metabolites, proteins and biomolecular pathways alterations in primary human IMR90 fibroblasts upon energy deficits. Multivariate statistical analyses revealed significant treatment-specific metabolite level and ratio alterations as well as major energy metabolism pathways like 'glycolysis', 'pentose phosphate pathway', 'mitochondrial electron transport chain' and 'protein biosynthesis (amino acids)' indicating an activation of catabolism and reduction of anabolism as important mechanisms of adaptation towards a bioenergetic demand...
February 5, 2018: Scientific Reports
Grover Bagby
Fanconi anemia is an inherited disease characterized by genomic instability, hypersensitivity to DNA cross-linking agents, bone marrow failure, short stature, skeletal abnormalities, and a high relative risk of myeloid leukemia and epithelial malignancies. The 21 Fanconi anemia genes encode proteins involved in multiple nuclear biochemical pathways that effect DNA interstrand crosslink repair. In the past, bone marrow failure was attributed solely to the failure of stem cells to repair DNA. Recently, non-canonical functions of many of the Fanconi anemia proteins have been described, including modulating responses to oxidative stress, viral infection, and inflammation as well as facilitating mitophagic responses and enhancing signals that promote stem cell function and survival...
2018: F1000Research
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