{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T11:17:47Z","timestamp":1785237467053,"version":"3.55.0"},"reference-count":77,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,10,10]],"date-time":"2022-10-10T00:00:00Z","timestamp":1665360000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81870657"],"award-info":[{"award-number":["81870657"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2022A1515012168"],"award-info":[{"award-number":["2022A1515012168"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2020YFA0112701"],"award-info":[{"award-number":["2020YFA0112701"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Natural Science Foundation of Guangdong Province of China","award":["81870657"],"award-info":[{"award-number":["81870657"]}]},{"name":"Natural Science Foundation of Guangdong Province of China","award":["2022A1515012168"],"award-info":[{"award-number":["2022A1515012168"]}]},{"name":"Natural Science Foundation of Guangdong Province of China","award":["2020YFA0112701"],"award-info":[{"award-number":["2020YFA0112701"]}]},{"name":"National Key Research and Development Project of China","award":["81870657"],"award-info":[{"award-number":["81870657"]}]},{"name":"National Key Research and Development Project of China","award":["2022A1515012168"],"award-info":[{"award-number":["2022A1515012168"]}]},{"name":"National Key Research and Development Project of China","award":["2020YFA0112701"],"award-info":[{"award-number":["2020YFA0112701"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Retinal ganglion cells (RGCs), the projection neurons of the eye, are irreversibly lost once the optic nerve is injured, which is a critical mechanism of glaucoma. Mobile zinc (Zn2+) levels rapidly increase in retinal interneuron amacrine cells and Zn2+ is then transferred to RGCs via the Zn2+ transporter protein ZnT-3, triggering RGC loss in optic nerve injury. Zn2+ chelation and ZnT-3 deletion promote long-term RGC survival. However, the downstream signaling pathways of Zn2+ in RGCs remains unknown. Here, we show that increased levels of Zn2+ upregulate the expression and activity of mitochondrial zinc metallopeptidase OMA1 in the retina, leading to the cleavage of DELE1 and activation of cytosolic eIF2\u03b1 kinase PKR, triggering the integrated stress response (ISR) in RGCs. Our study identified OMA1 and ISR as the downstream molecular mechanisms of retinal Zn2+ and potential targets for preventing the progression of Zn2+-associated neuronal damage.<\/jats:p>","DOI":"10.3390\/antiox11102001","type":"journal-article","created":{"date-parts":[[2022,10,10]],"date-time":"2022-10-10T21:07:11Z","timestamp":1665436031000},"page":"2001","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Increased Mobile Zinc Regulates Retinal Ganglion Cell Survival via Activating Mitochondrial OMA1 and Integrated Stress Response"],"prefix":"10.3390","volume":"11","author":[{"given":"Jiahui","family":"Tang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxu","family":"Han","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingfei","family":"Xue","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liyan","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jicheng","family":"Lin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caiqing","family":"Wu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siting","family":"Wu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Canying","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haishun","family":"Huang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Fu","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5657-8675","authenticated-orcid":false,"given":"Min","family":"Li","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yehong","family":"Zhuo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiqing","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2183","DOI":"10.1016\/S0140-6736(17)31469-1","article-title":"Glaucoma","volume":"390","author":"Jonas","year":"2017","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/j.expneurol.2015.12.015","article-title":"Reaching the brain: Advances in optic nerve regeneration","volume":"287","author":"Benowitz","year":"2017","journal-title":"Exp. Neurol."},{"key":"ref_3","first-page":"E209","article-title":"Mobile zinc increases rapidly in the retina after optic nerve injury and regulates ganglion cell survival and optic nerve regeneration","volume":"114","author":"Li","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"666798","DOI":"10.3389\/fncel.2021.666798","article-title":"Non-Cell-Autonomous Regulation of Optic Nerve Regeneration by Amacrine Cells","volume":"15","author":"Sergeeva","year":"2021","journal-title":"Front. Cell. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.expneurol.2017.10.025","article-title":"Zinc chelation and Klf9 knockdown cooperatively promote axon regeneration after optic nerve injury","volume":"300","author":"Trakhtenberg","year":"2018","journal-title":"Exp. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1146\/annurev-vision-022720-094953","article-title":"Axon Regeneration in the Mammalian Optic Nerve","volume":"6","author":"Williams","year":"2020","journal-title":"Annu. Rev. Vis. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"K\u00fchlbrandt, W. (2015). Structure and function of mitochondrial membrane protein complexes. BMC Biol., 13.","DOI":"10.1186\/s12915-015-0201-x"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1038\/nrm2275","article-title":"Functions and dysfunctions of mitochondrial dynamics","volume":"8","author":"Detmer","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/s41580-018-0092-0","article-title":"Mitochondrial proteins: From biogenesis to functional networks","volume":"20","author":"Pfanner","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Kang, E., Liu, P., Wen, Y., Quinn, P., Levi, S., Wang, N., and Tsai, R. (2021). Role of Oxidative Stress in Ocular Diseases Associated with Retinal Ganglion Cells Degeneration. Antioxidants, 10.","DOI":"10.3390\/antiox10121948"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"720288","DOI":"10.3389\/fcell.2021.720288","article-title":"Effects of Iron and Zinc on Mitochondria: Potential Mechanisms of Glaucomatous Injury","volume":"9","author":"Tang","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1126\/science.aal0092","article-title":"Vitamin B modulates mitochondrial vulnerability and prevents glaucoma in aged mice","volume":"355","author":"Williams","year":"2017","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"101988","DOI":"10.1016\/j.redox.2021.101988","article-title":"Nicotinamide provides neuroprotection in glaucoma by protecting against mitochondrial and metabolic dysfunction","volume":"43","author":"Tribble","year":"2021","journal-title":"Redox Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1146\/annurev-biochem-062917-012739","article-title":"Mitochondrial Proteases: Multifaceted Regulators of Mitochondrial Plasticity","volume":"89","author":"Deshwal","year":"2020","journal-title":"Annu. Rev. Biochem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1523\/JNEUROSCI.2225-10.2011","article-title":"The mitochondrial permeability transition pore regulates nitric oxide-mediated apoptosis of neurons induced by target deprivation","volume":"31","author":"Martin","year":"2011","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"113161","DOI":"10.1016\/j.expneurol.2019.113161","article-title":"Zn entry through the mitochondrial calcium uniporter is a critical contributor to mitochondrial dysfunction and neurodegeneration","volume":"325","author":"Ji","year":"2020","journal-title":"Exp. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e2023909118","DOI":"10.1073\/pnas.2023909118","article-title":"SLC-30A9 is required for Zn homeostasis, Zn mobilization, and mitochondrial health","volume":"118","author":"Deng","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1523\/JNEUROSCI.4604-08.2009","article-title":"Intracellular Zn2+ accumulation contributes to synaptic failure, mitochondrial depolarization, and cell death in an acute slice oxygen-glucose deprivation model of ischemia","volume":"29","author":"Medvedeva","year":"2009","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"46414","DOI":"10.1074\/jbc.M305584200","article-title":"Oma1, a novel membrane-bound metallopeptidase in mitochondria with activities overlapping with the m-AAA protease","volume":"278","author":"Kaser","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"140558","DOI":"10.1016\/j.bbapap.2020.140558","article-title":"OMA1-An integral membrane protease?","volume":"1869","author":"Alavi","year":"2021","journal-title":"Biochim. Et Biophys. Acta. Proteins Proteom."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2966","DOI":"10.1038\/sj.emboj.7601184","article-title":"Regulation of mitochondrial morphology through proteolytic cleavage of OPA1","volume":"25","author":"Ishihara","year":"2006","journal-title":"EMBO J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1083\/jcb.200906083","article-title":"Inducible proteolytic inactivation of OPA1 mediated by the OMA1 protease in mammalian cells","volume":"187","author":"Head","year":"2009","journal-title":"J. Cell Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2297","DOI":"10.1242\/jcs.159186","article-title":"OPA1 processing in cell death and disease\u2014The long and short of it","volume":"129","author":"MacVicar","year":"2016","journal-title":"J. Cell Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"jcs213546","DOI":"10.1242\/jcs.213546","article-title":"m-AAA and i-AAA complexes coordinate to regulate OMA1, the stress-activated supervisor of mitochondrial dynamics","volume":"131","author":"Consolato","year":"2018","journal-title":"J. Cell Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"14782","DOI":"10.1073\/pnas.1417253111","article-title":"Activation of mitochondrial protease OMA1 by Bax and Bak promotes cytochrome c release during apoptosis","volume":"111","author":"Jiang","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"eaan4935","DOI":"10.1126\/scitranslmed.aan4935","article-title":"Ablation of the stress protease OMA1 protects against heart failure in mice","volume":"10","author":"Torroja","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1083\/jcb.201507022","article-title":"Loss of OMA1 delays neurodegeneration by preventing stress-induced OPA1 processing in mitochondria","volume":"212","author":"Korwitz","year":"2016","journal-title":"J. Cell Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1038\/s41586-020-2078-2","article-title":"Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway","volume":"579","author":"Guo","year":"2020","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1038\/s41586-020-2076-4","article-title":"A pathway coordinated by DELE1 relays mitochondrial stress to the cytosol","volume":"579","author":"Fessler","year":"2020","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"24961","DOI":"10.1074\/jbc.M115.673343","article-title":"Death-associated Protein 3 Regulates Mitochondrial-encoded Protein Synthesis and Mitochondrial Dynamics","volume":"290","author":"Xiao","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_31","first-page":"188","article-title":"Mammalian dap3 is an essential gene required for mitochondrial homeostasis in vivo and contributing to the extrinsic pathway for apoptosis","volume":"21","author":"Kim","year":"2007","journal-title":"FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1007\/s10495-010-0519-3","article-title":"Identification of DELE, a novel DAP3-binding protein which is crucial for death receptor-mediated apoptosis induction","volume":"15","author":"Harada","year":"2010","journal-title":"Apoptosis Int. J. Program. Cell Death"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1038\/s41467-022-29479-y","article-title":"DELE1 tracks perturbed protein import and processing in human mitochondria","volume":"13","author":"Fessler","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"eaat5314","DOI":"10.1126\/science.aat5314","article-title":"The integrated stress response: From mechanism to disease","volume":"368","author":"Walter","year":"2020","journal-title":"Science"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1126\/science.abb3414","article-title":"The integrated stress response contributes to tRNA synthetase-associated peripheral neuropathy","volume":"373","author":"Spaulding","year":"2021","journal-title":"Science"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1038\/s41418-020-00688-6","article-title":"Activating transcription factor-4 promotes neuronal death induced by Parkinson's disease neurotoxins and \u03b1-synuclein aggregates","volume":"28","author":"Demmings","year":"2021","journal-title":"Cell Death Differ."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e62048","DOI":"10.7554\/eLife.62048","article-title":"Small molecule cognitive enhancer reverses age-related memory decline in mice","volume":"9","author":"Krukowski","year":"2020","journal-title":"eLife"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.1038\/s41418-022-00967-4","article-title":"Inhibition of cGAS-STING by JQ1 alleviates oxidative stress-induced retina inflammation and degeneration","volume":"29","author":"Zou","year":"2022","journal-title":"Cell Death Differ."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"19587","DOI":"10.1073\/pnas.0907085106","article-title":"Oncomodulin links inflammation to optic nerve regeneration","volume":"106","author":"Yin","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mito.2019.03.001","article-title":"The first direct activity assay for the mitochondrial protease OMA1","volume":"46","author":"Tobacyk","year":"2019","journal-title":"Mitochondrion"},{"key":"ref_41","first-page":"e55785","article-title":"Isolation of Primary Murine Retinal Ganglion Cells (RGCs) by Flow Cytometry","volume":"125","author":"Chintalapudi","year":"2017","journal-title":"J. Vis. Exp."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/0003-2697(87)90021-2","article-title":"Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction","volume":"162","author":"Chomczynski","year":"1987","journal-title":"Anal. Biochem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"626117","DOI":"10.3389\/fcell.2021.626117","article-title":"Mitochondrial OMA1 and OPA1 as Gatekeepers of Organellar Structure\/Function and Cellular Stress Response","volume":"9","author":"Gilkerson","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"100799","DOI":"10.1016\/j.preteyeres.2019.100799","article-title":"Inducible rodent models of glaucoma","volume":"75","author":"Pang","year":"2020","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1038\/s41586-020-2975-4","article-title":"Reprogramming to recover youthful epigenetic information and restore vision","volume":"588","author":"Lu","year":"2020","journal-title":"Nature"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1083\/jcb.200704112","article-title":"Regulation of the mitochondrial dynamin-like protein Opa1 by proteolytic cleavage","volume":"178","author":"Griparic","year":"2007","journal-title":"J. Cell Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2202","DOI":"10.1021\/acschembio.1c00350","article-title":"OMA1 High-Throughput Screen Reveals Protease Activation by Kinase Inhibitors","volume":"16","author":"Alavi","year":"2021","journal-title":"ACS Chem. Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"106063","DOI":"10.1016\/j.phrs.2022.106063","article-title":"Recent advances in, and challenges of, designing OMA1 drug screens","volume":"176","author":"Alavi","year":"2022","journal-title":"Pharmacol. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1002\/embj.201386474","article-title":"Stress-induced OMA1 activation and autocatalytic turnover regulate OPA1-dependent mitochondrial dynamics","volume":"33","author":"Baker","year":"2014","journal-title":"EMBO J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1002\/embr.201338240","article-title":"Membrane depolarization activates the mitochondrial protease OMA1 by stimulating self-cleavage","volume":"15","author":"Zhang","year":"2014","journal-title":"EMBO Rep."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/s41419-022-04782-0","article-title":"Ischemia-induced cleavage of OPA1 at S1 site aggravates mitochondrial fragmentation and reperfusion injury in neurons","volume":"13","author":"Li","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e157504","DOI":"10.1172\/JCI157504","article-title":"OMA1 mediates local and global stress responses against protein misfolding in CHCHD10 mitochondrial myopathy","volume":"132","author":"Shammas","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e10575","DOI":"10.7554\/eLife.10575","article-title":"Mitochondrial dysfunction remodels one-carbon metabolism in human cells","volume":"5","author":"Bao","year":"2016","journal-title":"eLife"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2027","DOI":"10.1083\/jcb.201702058","article-title":"Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals","volume":"216","author":"Prado","year":"2017","journal-title":"J. Cell Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e72593","DOI":"10.7554\/eLife.72593","article-title":"Disruption of the TCA cycle reveals an ATF4-dependent integration of redox and amino acid metabolism","volume":"10","author":"Ryan","year":"2021","journal-title":"eLife"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3366","DOI":"10.1073\/pnas.1019166108","article-title":"Zinc transporter ZnT-3 regulates presynaptic Erk1\/2 signaling and hippocampus-dependent memory","volume":"108","author":"Sindreu","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1152\/physrev.00035.2014","article-title":"The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism","volume":"95","author":"Kambe","year":"2015","journal-title":"Physiol. Rev."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"4682","DOI":"10.1021\/cr800556u","article-title":"Coordination dynamics of zinc in proteins","volume":"109","author":"Maret","year":"2009","journal-title":"Chem. Rev."},{"key":"ref_59","unstructured":"Silva, J.J.R.F.d., and Williams, R.J.P. (2001). The Biological Chemistry of the Elements: The Inorganic Chemistry of Life, Oxford University Press. [2nd ed.]. pp. xvii."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1038\/nature08300","article-title":"Metalloproteins and metal sensing","volume":"460","author":"Waldron","year":"2009","journal-title":"Nature"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"21279","DOI":"10.1074\/jbc.M113.476580","article-title":"A novel family of soluble minimal scaffolds provides structural insight into the catalytic domains of integral membrane metallopeptidases","volume":"288","author":"Canals","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1896","DOI":"10.1038\/s41418-019-0469-4","article-title":"Prohibitin levels regulate OMA1 activity and turnover in neurons","volume":"27","author":"Anderson","year":"2020","journal-title":"Cell Death Differ."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.nbd.2016.07.003","article-title":"Zinc contributes to acute cerebral ischemia-induced blood-brain barrier disruption","volume":"95","author":"Qi","year":"2016","journal-title":"Neurobiol. Dis."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2942","DOI":"10.1093\/brain\/awq218","article-title":"Opa1 deficiency in a mouse model of dominant optic atrophy leads to retinal ganglion cell dendropathy","volume":"133","author":"Williams","year":"2010","journal-title":"Brain A J. Neurol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"350","DOI":"10.3389\/fnmol.2018.00350","article-title":"Overexpression of Optic Atrophy Type 1 Protects Retinal Ganglion Cells and Upregulates Parkin Expression in Experimental Glaucoma","volume":"11","author":"Hu","year":"2018","journal-title":"Front Mol Neurosci"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1016\/j.cmet.2015.04.016","article-title":"Opa1 overexpression ameliorates the phenotype of two mitochondrial disease mouse models","volume":"21","author":"Civiletto","year":"2015","journal-title":"Cell Metab."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1111\/cns.12428","article-title":"The Zinc Ion Chelating Agent TPEN Attenuates Neuronal Death\/apoptosis Caused by Hypoxia\/ischemia Via Mediating the Pathophysiological Cascade Including Excitotoxicity, Oxidative Stress, and Inflammation","volume":"21","author":"Wang","year":"2015","journal-title":"CNS Neurosci. Ther."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.expneurol.2015.04.005","article-title":"Reduction of zinc accumulation in mitochondria contributes to decreased cerebral ischemic injury by normobaric hyperoxia treatment in an experimental stroke model","volume":"272","author":"Dong","year":"2015","journal-title":"Exp. Neurol."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Genin, E., Bannwarth, S., Ropert, B., Lespinasse, F., Mauri-Crouzet, A., Aug\u00e9, G., Fragaki, K., Cochaud, C., Donnarumma, E., and Lacas-Gervais, S. (2022). CHCHD10 and SLP2 control the stability of the PHB complex: A key factor for motor neuron viability. Brain A J. Neurol.","DOI":"10.1093\/brain\/awac197"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1038\/s41419-022-04602-5","article-title":"CHCHD2 and CHCHD10 regulate mitochondrial dynamics and integrated stress response","volume":"13","author":"Ruan","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Cheng, M., Yu, H., Kong, Q., Wang, B., Shen, L., Dong, D., and Sun, L. (2022). The Mitochondrial PHB2\/OMA1\/DELE1 Pathway Cooperates with Endoplasmic Reticulum Stress to Facilitate the Response to Chemotherapeutics in Ovarian Cancer. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031320"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1038\/nsmb.1529","article-title":"Rapid evolution of protein kinase PKR alters sensitivity to viral inhibitors","volume":"16","author":"Rothenburg","year":"2009","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1016\/j.molcel.2018.07.029","article-title":"PKR Senses Nuclear and Mitochondrial Signals by Interacting with Endogenous Double-Stranded RNAs","volume":"71","author":"Kim","year":"2018","journal-title":"Mol. Cell"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"e202111100","DOI":"10.1083\/jcb.202111100","article-title":"Signaling by the integrated stress response kinase PKR is fine-tuned by dynamic clustering","volume":"221","author":"Zappa","year":"2022","journal-title":"J. Cell Biol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e14295","DOI":"10.7554\/eLife.14295","article-title":"Activation of GCN2 kinase by ribosome stalling links translation elongation with translation initiation","volume":"5","author":"Ishimura","year":"2016","journal-title":"eLife"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/s41419-020-2601-2","article-title":"Fine tuning of the unfolded protein response by ISRIB improves neuronal survival in a model of amyotrophic lateral sclerosis","volume":"11","author":"Bugallo","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"eabc5429","DOI":"10.1126\/scisignal.abc5429","article-title":"Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity, and memory in mouse models of Alzheimer's disease","volume":"14","author":"Oliveira","year":"2021","journal-title":"Sci. Signal."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/11\/10\/2001\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:49:07Z","timestamp":1760143747000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/11\/10\/2001"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,10]]},"references-count":77,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,10]]}},"alternative-id":["antiox11102001"],"URL":"https:\/\/doi.org\/10.3390\/antiox11102001","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,10]]}}}