{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T18:14:27Z","timestamp":1789582467000,"version":"build-2803163510"},"reference-count":93,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,4,13]],"date-time":"2023-04-13T00:00:00Z","timestamp":1681344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Arts and Sciences Dean\u2019s Office and the Office of Foundation, Government, and Corporate Grants at Oberlin College"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Exposure to heavy metals, including cadmium (Cd), can induce neurotoxicity and cell death. Cd is abundant in the environment and accumulates in the striatum, the primary brain region selectively affected by Huntington\u2019s disease (HD). We have previously reported that mutant huntingtin protein (mHTT) combined with chronic Cd exposure induces oxidative stress and promotes metal dyshomeostasis, resulting in cell death in a striatal cell model of HD. To understand the effect of acute Cd exposure on mitochondrial health and protein degradation pathways, we hypothesized that expression of mHTT coupled with acute Cd exposure would cooperatively alter mitochondrial bioenergetics and protein degradation mechanisms in striatal STHdh cells to reveal novel pathways that augment Cd cytotoxicity and HD pathogenicity. We report that mHTT cells are significantly more susceptible to acute Cd-induced cell death as early as 6 h after 40 \u00b5M CdCl2 exposure compared with wild-type (WT). Confocal microscopy, biochemical assays, and immunoblotting analysis revealed that mHTT and acute Cd exposure synergistically impair mitochondrial bioenergetics by reducing mitochondrial potential and cellular ATP levels and down-regulating the essential pro-fusion proteins MFN1 and MFN2. These pathogenic effects triggered cell death. Furthermore, Cd exposure increases the expression of autophagic markers, such as p62, LC3, and ATG5, and reduces the activity of the ubiquitin\u2013proteasome system to promote neurodegeneration in HD striatal cells. Overall, these results reveal a novel mechanism to further establish Cd as a pathogenic neuromodulator in striatal HD cells via Cd-triggered neurotoxicity and cell death mediated by an impairment in mitochondrial bioenergetics and autophagy with subsequent alteration in protein degradation pathways.<\/jats:p>","DOI":"10.3390\/ijms24087178","type":"journal-article","created":{"date-parts":[[2023,4,13]],"date-time":"2023-04-13T02:29:15Z","timestamp":1681352955000},"page":"7178","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Defective Mitochondrial Dynamics and Protein Degradation Pathways Underlie Cadmium-Induced Neurotoxicity and Cell Death in Huntington\u2019s Disease Striatal Cells"],"prefix":"10.3390","volume":"24","author":[{"given":"Paul J.","family":"Kamitsuka","sequence":"first","affiliation":[{"name":"Neuroscience Department, Oberlin College, 119 Woodland Street, Oberlin, OH 44074, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0924-459X","authenticated-orcid":false,"given":"Marwan M.","family":"Ghanem","sequence":"additional","affiliation":[{"name":"Neuroscience Department, Oberlin College, 119 Woodland Street, Oberlin, OH 44074, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rania","family":"Ziar","sequence":"additional","affiliation":[{"name":"Neuroscience Department, Oberlin College, 119 Woodland Street, Oberlin, OH 44074, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3988-9174","authenticated-orcid":false,"given":"Sarah E.","family":"McDonald","sequence":"additional","affiliation":[{"name":"Neuroscience Department, Oberlin College, 119 Woodland Street, Oberlin, OH 44074, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7807-9703","authenticated-orcid":false,"given":"Morgan G.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Neuroscience Department, Oberlin College, 119 Woodland Street, Oberlin, OH 44074, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9486-2044","authenticated-orcid":false,"given":"Gunnar F.","family":"Kwakye","sequence":"additional","affiliation":[{"name":"Neuroscience Department, Oberlin College, 119 Woodland Street, Oberlin, OH 44074, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-3-319-71779-1_1","article-title":"Clinical features of huntington\u2019s disease","volume":"1049","author":"Ghosh","year":"2018","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1038\/35039051","article-title":"Molecular genetics: Unmasking polyglutamine triggers in neurodegenerative disease","volume":"1","author":"Gusella","year":"2000","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1515\/BC.2000.114","article-title":"Protein aggregation and pathogenesis of Huntington\u2019s disease: Mechanisms and correlations","volume":"381","author":"Wanker","year":"2000","journal-title":"Biol. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4830","DOI":"10.1093\/hmg\/ddp455","article-title":"Selective Neuronal Requirement for Huntingtin in the Developing Zebrafish","volume":"18","author":"Henshall","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"10720","DOI":"10.1523\/JNEUROSCI.2126-08.2008","article-title":"Huntingtin modulates transcription, occupies gene promoters in vivo, and binds directly to DNA in a polyglutamine-dependent manner","volume":"28","author":"Benn","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"8195","DOI":"10.1128\/MCB.24.18.8195-8209.2004","article-title":"Mutant Huntingtin Impairs Axonal Trafficking in Mammalian Neurons In Vivo and In Vitro","volume":"24","author":"Trushina","year":"2004","journal-title":"Mol. Cell. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.jtemb.2011.08.144","article-title":"Role of manganese in neurodegenerative diseases","volume":"25","author":"Bowman","year":"2011","journal-title":"J. Trace Elem. Med. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"689332","DOI":"10.3389\/fncel.2021.689332","article-title":"Huntingtin and the synapse","volume":"15","author":"Barron","year":"2021","journal-title":"Front. Cell. Neurosci."},{"key":"ref_9","first-page":"65","article-title":"The biological function of the Huntingtin protein and its relevance to Huntington\u2019s Disease pathology","volume":"5","author":"Schulte","year":"2011","journal-title":"Curr. Trends Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e83","DOI":"10.1093\/nar\/gnf082","article-title":"Counting CAG repeats in the Huntington\u2019s disease gene by restriction endonuclease EcoP15I cleavage","volume":"30","author":"Reich","year":"2002","journal-title":"Nucleic Acids Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/j.nbd.2005.05.017","article-title":"Progressive and selective striatal degeneration in primary neuronal cultures using lentiviral vector coding for a mutant huntingtin fragment","volume":"20","author":"Zala","year":"2005","journal-title":"Neurobiol. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1021\/pr200839d","article-title":"Changes in the striatal proteome of YAC128Q mice exhibit gene-environment interactions between mutant huntingtin and manganese","volume":"11","author":"Wegrzynowicz","year":"2012","journal-title":"J. Proteome Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.neuro.2018.10.012","article-title":"Heterozygous huntingtin promotes cadmium neurotoxicity and neurodegeneration in striatal cells via altered metal transport and protein kinase C delta dependent oxidative stress and apoptosis signaling mechanisms","volume":"70","author":"Kwakye","year":"2019","journal-title":"Neurotoxicology"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Fox, J.H., Kama, J.A., Lieberman, G., Chopra, R., Dorsey, K., Chopra, V., Volitakis, I., Cherny, R.A., Bush, A.I., and Hersch, S. (2007). Mechanisms of Copper Ion Mediated Huntington\u2019s Disease Progression. PLoS ONE, 2.","DOI":"10.1371\/journal.pone.0000334"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1111\/j.1471-4159.2009.06445.x","article-title":"Disease-toxicant screen reveals a neuroprotective interaction between Huntington\u2019s disease and manganese exposure","volume":"112","author":"Williams","year":"2010","journal-title":"J. Neurochem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"E3446","DOI":"10.1073\/pnas.1717978115","article-title":"Molecular and structural architecture of polyQ aggregates in yeast","volume":"115","author":"Gruber","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/S1474-4422(10)70245-3","article-title":"Huntington\u2019s disease: From molecular pathogenesis to clinical treatment","volume":"10","author":"Ross","year":"2011","journal-title":"Lancet Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1042\/EBC20170104","article-title":"Mitochondrial dynamics: Overview of molecular mechanisms","volume":"62","author":"Tilokani","year":"2018","journal-title":"Essays Biochem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1016\/j.bbabio.2008.05.001","article-title":"Mitochondrial fusion, fission and autophagy as a quality control axis: The bioenergetic view","volume":"1777","author":"Twig","year":"2008","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1016\/j.mito.2010.08.005","article-title":"Mitochondrial Fission\/Fusion Dynamics and Apoptosis","volume":"10","author":"Sheridan","year":"2010","journal-title":"Mitochondrion"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.nbd.2015.09.008","article-title":"Mitochondrial dynamics and quality control in Huntington\u2019s disease","volume":"90","author":"Pinho","year":"2016","journal-title":"Neurobiol. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"541040","DOI":"10.3389\/fphys.2020.541040","article-title":"The functional impact of mitochondrial structure across subcellular scales","volume":"11","author":"Glancy","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1111\/febs.13820","article-title":"Mitochondrial biogenesis and clearance: A balancing act","volume":"284","author":"Ploumi","year":"2017","journal-title":"FEBS J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1002\/path.2697","article-title":"Autophagy: Cellular and molecular mechanisms","volume":"221","author":"Glick","year":"2010","journal-title":"J. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1146\/annurev.biochem.67.1.425","article-title":"The ubiquitin system","volume":"67","author":"Hershko","year":"1998","journal-title":"Annu. Rev. Biochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"849","DOI":"10.4161\/auto.6845","article-title":"Does bafilomycin A1block the fusion of autophagosomes with lysosomes?","volume":"4","author":"Klionsky","year":"2008","journal-title":"Autophagy"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2156","DOI":"10.1016\/j.febslet.2007.01.096","article-title":"Molecular machinery of autophagosome formation in yeast, Saccharomyces cerevisiae","volume":"581","author":"Suzuki","year":"2007","journal-title":"FEBS Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1038\/nature05291","article-title":"The roles of intracellular protein-degradation pathways in neurodegeneration","volume":"443","author":"Rubinsztein","year":"2006","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.neuropsychologia.2009.09.002","article-title":"Automaticity and attention in Huntington\u2019s disease: When two hands are not better than one","volume":"48","author":"Thompson","year":"2010","journal-title":"Neuropsychologia"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/S1097-2765(04)00151-0","article-title":"Eukaryotic Proteasomes Cannot Digest Polyglutamine Sequences and Release Them during Degradation of Polyglutamine-Containing Proteins","volume":"14","author":"Venkatraman","year":"2004","journal-title":"Mol. Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"303","DOI":"10.3389\/fnagi.2016.00303","article-title":"Dysregulation of Ubiquitin-Proteasome System in Neurodegenerative Diseases","volume":"8","author":"Zheng","year":"2016","journal-title":"Front. Aging Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"200","DOI":"10.3389\/fcell.2020.00200","article-title":"Mitophagy: An Emerging Role in Aging and Age-Associated Diseases","volume":"8","author":"Chen","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1146\/annurev-genet-102108-134850","article-title":"The role of mitochondria in apoptosis","volume":"43","author":"Wang","year":"2009","journal-title":"Annu. Rev. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1111\/j.1440-1681.2005.04313.x","article-title":"Gene-Environment Interactions, Neuronal Dysfunction and Pathological Plasticity in Huntington\u2019s Disease","volume":"32","author":"Grote","year":"2005","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.neubiorev.2015.03.003","article-title":"Environmental factors as modulators of neurodegeneration: Insights from gene-environment interactions in Huntington\u2019s disease","volume":"52","author":"Mo","year":"2015","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/s10048-003-0169-5","article-title":"Genetic and Environmental Factors in the Pathogenesis of Huntington\u2019s Disease","volume":"5","author":"Hannan","year":"2004","journal-title":"Neurogenetics"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.neuro.2017.03.004","article-title":"Acute exposure to chlorpyrifos caused NADPH oxidase mediated oxidative stress and neurotoxicity in a striatal cell model of Huntington\u2019s disease","volume":"60","author":"Dominah","year":"2017","journal-title":"Neurotoxicology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3498","DOI":"10.1073\/pnas.0308679101","article-title":"Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington\u2019s disease age of onset","volume":"101","author":"Wexler","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1136\/jmg.20.6.408","article-title":"Huntington\u2019s disease in monozygotic twins reared apart","volume":"20","author":"Sudarsky","year":"1983","journal-title":"J. Med. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1212\/WNL.25.12.1126","article-title":"Monozygotic twins with Huntington\u2019s disease in a family expressing the rigid variant","volume":"25","author":"Bird","year":"1975","journal-title":"Neurology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1002\/1531-8257(199903)14:2<320::AID-MDS1018>3.0.CO;2-Z","article-title":"Differential clinical and motor control function in a pair of monozygotic twins with Huntington\u2019s disease","volume":"14","author":"Georgiou","year":"1999","journal-title":"Mov. Disord."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.1093\/hmg\/ddm138","article-title":"Huntingtin-deficient zebrafish exhibit defects in iron utilization and development","volume":"16","author":"Lumsden","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1039\/d0mt00081g","article-title":"Huntington\u2019s disease genotype suppresses global manganese-responsive processes in pre-manifest and manifest YAC128 mice","volume":"12","author":"Pfalzer","year":"2020","journal-title":"Met. Integr. Biometal Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1953","DOI":"10.1093\/brain\/114.4.1953","article-title":"Alterations in the levels of iron, ferritin and other trace metals in Parkinson\u2019s disease and other neurodegenerative diseases affecting the basal ganglia","volume":"114","author":"Dexter","year":"1991","journal-title":"Brain A J. Neurol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"366","DOI":"10.12688\/f1000research.7431.1","article-title":"Metals and Neurodegeneration","volume":"5","author":"Chen","year":"2016","journal-title":"F1000Res"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.tox.2011.03.001","article-title":"Advances in metal-induced oxidative stress and human disease","volume":"283","author":"Jomova","year":"2011","journal-title":"Toxicology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"7519","DOI":"10.3390\/ijerph120707519","article-title":"Manganese-Induced Parkinsonism and Parkinson\u2019s Disease: Shared and Distinguishable Features","volume":"2","author":"Kwakye","year":"2015","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1111\/jnc.12739","article-title":"Iron dysregulation in Huntington\u2019s disease","volume":"130","author":"Muller","year":"2014","journal-title":"J. Neurochem."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Patel, R., and Aschner, M. (2021). Commonalities between Copper Neurotoxicity and Alzheimer\u2019s Disease. Toxics, 9.","DOI":"10.3390\/toxics9010004"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"104388","DOI":"10.1016\/j.apgeochem.2019.104388","article-title":"Cadmium in soils and groundwater: A review","volume":"108","author":"Kubier","year":"2019","journal-title":"Appl. Geochem."},{"key":"ref_51","unstructured":"Tucker, P. (2008). Cadmium toxicity, Case Studies in Environmental Medicine (CSEM)."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"18355","DOI":"10.1007\/s11356-020-08160-1","article-title":"Presence of cadmium and lead in tobacco and soil with ecological and human health risks in Sichuan province, China","volume":"27","author":"Proshad","year":"2020","journal-title":"Environ. Sci. Pollut. Res. Int."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1177\/153537020422900506","article-title":"Endocrine disruption by cadmium, a common environmental toxicant with paradoxical effects on reproduction","volume":"229","author":"Henson","year":"2004","journal-title":"Exp. Biol. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"898034","DOI":"10.1155\/2013\/898034","article-title":"Cadmium and its neurotoxic effects","volume":"2013","author":"Wang","year":"2013","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1016\/j.toxrep.2020.08.005","article-title":"Disruption of essential metal homeostasis in the brain by cadmium and high-fat diet","volume":"7","author":"Mazzocco","year":"2020","journal-title":"Toxicol. Rep."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.taap.2011.06.024","article-title":"Cadmium Induces Autophagy through ROS-Dependent Activation of the LKB1-AMPK Signaling in Skin Epidermal Cells","volume":"255","author":"Son","year":"2011","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1289\/ehp.6751","article-title":"Adverse Health Effects of Chronic Exposure to Low-Level Cadmium in Foodstuffs and Cigarette Smoke","volume":"112","author":"Satarug","year":"2004","journal-title":"Environ. Health Perspect."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.drugalcdep.2006.06.009","article-title":"Huntington disease as a dual diagnosis disorder: Data from the National Research Roster for Huntington disease patients and families","volume":"86","author":"Ehret","year":"2007","journal-title":"Drug Alcohol Depend."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1007\/s10863-010-9286-7","article-title":"The interrelationship between mitochondrial dysfunction and transcriptional dysregulation in Huntington disease","volume":"42","author":"Jin","year":"2010","journal-title":"J. Bioenerg. Biomembr."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/S0378-4274(03)00199-1","article-title":"Brain Regional Lipid Peroxidation and Metallothionein Levels of Developing Rats Exposed to Cadmium and Dexamethasone","volume":"144","author":"Mendezarmenta","year":"2003","journal-title":"Toxicol. Lett."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/15548627.2015.1100356","article-title":"Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)","volume":"12","author":"Klionsky","year":"2016","journal-title":"Autophagy"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/s12964-019-0353-3","article-title":"ATG5 and ATG7 induced autophagy interplays with UPR via PERK signaling","volume":"17","author":"Zheng","year":"2019","journal-title":"Cell Commun. Signal."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"77","DOI":"10.3389\/fnmol.2014.00077","article-title":"Ubiquitin-proteasome system involvement in Huntington\u2019s disease","volume":"7","author":"Ortega","year":"2014","journal-title":"Front. Mol. Neurosci."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/S0092-8674(00)80513-9","article-title":"Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation","volume":"90","author":"Davies","year":"1997","journal-title":"Cell"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1091\/mbc.12.5.1393","article-title":"Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation","volume":"12","author":"Waelter","year":"2001","journal-title":"Mol. Biol. Cell"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1093\/toxsci\/kfg009","article-title":"Cadmium uptake kinetics in rat hepatocytes: Correction for albumin binding","volume":"72","author":"DelRaso","year":"2003","journal-title":"Toxicol. Sci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1002\/(SICI)1099-1263(199605)16:3<227::AID-JAT337>3.0.CO;2-5","article-title":"Ontogenic profile of brain lipids following perinatal exposure to cadmium","volume":"16","author":"Gupta","year":"1996","journal-title":"J. Appl. Toxicol."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Genchi, G., Sinicropi, M.S., Lauria, G., Carocci, A., and Catalano, A. (2020). The effects of cadmium toxicity. Int. J. Environ. Res. Public Health, 17.","DOI":"10.3390\/ijerph17113782"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1046\/j.1460-9568.2003.02864.x","article-title":"Caspase-3 dependent proteolytic activation of protein kinase C\u03b4 mediates and regulates 1-methyl-4-phenylpyridinium (MPP+)-induced apoptotic cell death in dopaminergic cells: Relevance to oxidative stress in dopaminergic degeneration","volume":"18","author":"Kaul","year":"2003","journal-title":"Eur. J. Neurosci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/j.drudis.2014.03.020","article-title":"Increased mitochondrial fission and neuronal dysfunction in Huntingtons disease: Implications for molecular inhibitors of excessive mitochondrial fission","volume":"19","author":"Reddy","year":"2014","journal-title":"Drug Discov. Today"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"104741","DOI":"10.1016\/j.nbd.2020.104741","article-title":"Mitochondrial fission in Huntington\u2019s disease mouse striatum disrupts ER-mitochondria contacts leading to disturbances in Ca2+ efflux and Reactive Oxygen Species (ROS) homeostasis","volume":"136","author":"Cherubini","year":"2020","journal-title":"Neurobiol. Dis."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/nm.2313","article-title":"Mutant Huntingtin Binds the Mitochondrial Fission GTPase Dynamin-Related Protein-1 and Increases Its Enzymatic Activity","volume":"17","author":"Song","year":"2011","journal-title":"Nat. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"545","DOI":"10.18388\/abp.2004_3590","article-title":"Cd2+-promoted mitochondrial permeability transition: A comparison with other heavy metals","volume":"51","author":"Belyaeva","year":"2004","journal-title":"Acta Biochim. Pol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1016\/j.cmet.2017.03.009","article-title":"The enigma of the respiratory chain supercomplex","volume":"25","author":"Milenkovic","year":"2017","journal-title":"Cell Metab."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e540","DOI":"10.1038\/cddis.2013.7","article-title":"Cadmium induced Drp1-dependent mitochondrial fragmentation by disturbing calcium homeostasis in its hepatotoxicity","volume":"4","author":"Xu","year":"2013","journal-title":"Cell Death Dis."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1016\/j.scitotenv.2019.06.405","article-title":"Cadmium exposure triggers mitochondrial dysfunction and oxidative stress in chicken (Gallus gallus) kidney via mitochondrial UPR inhibition and Nrf2-mediated antioxidant defense activation","volume":"689","author":"Ge","year":"2019","journal-title":"Sci. Total Environ."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.1093\/hmg\/ddr024","article-title":"Abnormal mitochondrial dynamics, mitochondrial loss and mutant huntingtin oligomers in Huntington\u2019s disease: Implications for selective neuronal damage","volume":"20","author":"Shirendeb","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1186\/1471-2091-8-S1-S2","article-title":"The ubiquitin proteasome system in Huntington\u2019s disease and the spinocerebellar ataxias","volume":"8","author":"Davies","year":"2007","journal-title":"BMC Biochem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1093\/hmg\/ddm023","article-title":"Extended polyglutamine repeats trigger a feedback loop involving the mitochondrial complex III, the proteasome and huntingtin aggregates","volume":"16","author":"Fukui","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1093\/jnen\/62.1.14","article-title":"Transglutaminase cross-links in intranuclear inclusions in Huntington disease","volume":"62","author":"Zainelli","year":"2003","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1093\/toxsci\/kfn087","article-title":"Cadmium-induced activation of stress signaling pathways, disruption of ubiquitin-dependent protein degradation and apoptosis in primary rat Sertoli cell-gonocyte cocultures","volume":"104","author":"Yu","year":"2008","journal-title":"Toxicol. Sci."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s11658-016-0031-z","article-title":"p62 links the autophagy pathway and the ubiqutin-proteasome system upon ubiquitinated protein degradation","volume":"21","author":"Liu","year":"2016","journal-title":"Cell. Mol. Biol. Lett."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1515\/hsz-2012-0119","article-title":"Mitophagy: Mechanisms, pathophysiological roles, and analysis","volume":"393","author":"Ding","year":"2012","journal-title":"Biol. Chem."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.4161\/auto.6.8.13617","article-title":"Early alterations of autophagy in Huntington disease-like mice","volume":"6","author":"Heng","year":"2010","journal-title":"Autophagy"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1016\/j.micinf.2009.08.013","article-title":"Major cell death pathways at a glance","volume":"11","author":"Duprez","year":"2009","journal-title":"Microbes Infect."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2799","DOI":"10.1093\/hmg\/9.19.2799","article-title":"Dominant phenotypes produced by the HD mutation in STHdh(Q111) striatal cells","volume":"9","author":"Trettel","year":"2000","journal-title":"Hum. Mol. Genet."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1016\/j.neuro.2011.01.002","article-title":"Novel high-throughput assay to assess cellular manganese levels in a striatal cell line model of Huntington\u2019s disease confirms a deficit in manganese accumulation","volume":"32","author":"Kwakye","year":"2011","journal-title":"Neurotoxicology"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.neuro.2017.07.026","article-title":"Phosphatidylinositol 3 kinase (PI3K) modulates manganese homeostasis and manganese-induced cell signaling in a murine striatal cell line","volume":"64","author":"Bryan","year":"2018","journal-title":"Neurotoxicology"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"3825","DOI":"10.1093\/hmg\/ddz209","article-title":"Acute manganese treatment restores defective autophagic cargo loading in Huntington\u2019s disease cell lines","volume":"28","author":"Bryan","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1007\/s12035-019-01824-1","article-title":"Manganese Acts upon Insulin\/IGF Receptors to Phosphorylate AKT and Increase Glucose Uptake in Huntington\u2019s Disease Cells","volume":"57","author":"Bryan","year":"2020","journal-title":"Mol. Neurobiol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.neuro.2022.06.004","article-title":"Ketamine-induced neurotoxicity is mediated through endoplasmic reticulum stress in vitro in STHdhQ7\/Q7 cells","volume":"91","author":"Rigg","year":"2022","journal-title":"Neurotoxicology"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1073\/pnas.97.2.889","article-title":"Atm and Bax cooperate in ionizing radiation-induced apoptosis in the central nervous system","volume":"97","author":"Chong","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"11753","DOI":"10.1074\/jbc.M208641200","article-title":"Aggregated and monomeric alpha-synuclein bind to the S6\u2019 proteasomal protein and inhibit proteasomal function","volume":"278","author":"Snyder","year":"2003","journal-title":"J. Biol. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/8\/7178\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:15:07Z","timestamp":1760123707000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/8\/7178"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,13]]},"references-count":93,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["ijms24087178"],"URL":"https:\/\/doi.org\/10.3390\/ijms24087178","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,13]]}}}