{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T12:28:09Z","timestamp":1784723289149,"version":"3.55.0"},"reference-count":36,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2018,1,3]],"date-time":"2018-01-03T00:00:00Z","timestamp":1514937600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100007351","name":"Secretaria de Ciencia y Tecnica, Universidad de Buenos Aires","doi-asserted-by":"publisher","award":["20720120200016BA"],"award-info":[{"award-number":["20720120200016BA"]}],"id":[{"id":"10.13039\/501100007351","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002923","name":"Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas","doi-asserted-by":"publisher","award":["PIP 11220090100199"],"award-info":[{"award-number":["PIP 11220090100199"]}],"id":[{"id":"10.13039\/501100002923","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Basic Clin Pharma Tox"],"published-print":{"date-parts":[[2018,5]]},"abstract":"Abstract<\/jats:title>Collapse of the mitochondrial membrane potential (MMP<\/jats:styled-content>) is often considered the initiation of regulated cell death (RCD<\/jats:styled-content>). Carbonyl cyanide 3\u2010chlorophenylhydrazone (CCCP<\/jats:styled-content>) is an uncoupler of the electron transport chain (ETC<\/jats:styled-content>) that facilitates the translocation of protons into the mitochondrial matrix leading to the collapse of the MMP<\/jats:styled-content>. Several cell stress responses such as mitophagy, mitochondrial biogenesis and the ubiquitin proteasome system may differentially contribute to restrain the initiation of RCD<\/jats:styled-content> depending on the extent of mitochondrial damage. We induced graded mitochondrial damage after collapse of MMP<\/jats:styled-content> with the mitochondrial uncoupler CCCP<\/jats:styled-content> in Burkitt's lymphoma cells, and we evaluated the effect of several drugs targeting cell stress responses over RCD<\/jats:styled-content> at 72\u00a0hr, using a multiparametric flow cytometry approach. CCCP<\/jats:styled-content> caused collapse of MMP<\/jats:styled-content> after 30\u00a0min., massive mitochondrial fission, oxidative stress and increased mitophagy within the 5\u201315\u00a0\u03bcM low\u2010dose range (LDR<\/jats:styled-content>) of CCCP<\/jats:styled-content>. Within the 20\u201350\u00a0\u03bcM high\u2010dose range (HDR<\/jats:styled-content>), CCCP<\/jats:styled-content> caused lysosomal destabilization and rupture, thus precluding mitophagy and autophagy. Cell death after 72\u00a0hr was below 20%, with increased mitochondrial mass (MM<\/jats:styled-content>). The inhibitors of mitophagy 3\u2010(2,4\u2010dichloro\u20105\u2010methoxyphenyl)\u20102,3\u2010dihydro\u20102\u2010thioxo\u20104(1H)\u2010quinazolinone (Mdivi\u20101) and vincristine (VCR<\/jats:styled-content>) increased cell death from CCCP<\/jats:styled-content> within the LDR<\/jats:styled-content>, while valproic acid (an inducer of mitochondrial biogenesis) also increased MM<\/jats:styled-content> and cell death within the LDR<\/jats:styled-content>. The proteasome inhibitor, MG<\/jats:styled-content>132, increased cell death only in the HDR<\/jats:styled-content>. Doxycycline, an antibiotic that disrupts mitochondrial biogenesis, had no effect on cell survival, while iodoacetamide, an inhibitor of glycolysis, increased cell death at the HDR<\/jats:styled-content>. We conclude that mitophagy influenced RCD<\/jats:styled-content> of lymphoma cells after MMP<\/jats:styled-content> collapse by CCCP<\/jats:styled-content> only within the LDR<\/jats:styled-content>, while proteasome activity and glycolysis contributed to survival in the HDR<\/jats:styled-content> under extensive mitochondria and lysosome damage.<\/jats:p>","DOI":"10.1111\/bcpt.12945","type":"journal-article","created":{"date-parts":[[2017,12,5]],"date-time":"2017-12-05T11:33:45Z","timestamp":1512473625000},"page":"489-500","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Regulated Cell Death of Lymphoma Cells after Graded Mitochondrial Damage is Differentially Affected by Drugs Targeting Cell Stress Responses"],"prefix":"10.1111","volume":"122","author":[{"given":"Tom\u00e1s","family":"Lombardo","sequence":"first","affiliation":[{"name":"Laboratory of Immunotoxicology (LaITo), IDEHU\u2010CONICET, Clinics Hospital, Jos\u00e9 de San Mart\u00edn University of Buenos Aires (UBA) Buenos Aires Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mart\u00edn Gil","family":"Folgar","sequence":"additional","affiliation":[{"name":"Laboratory of Immunotoxicology (LaITo), IDEHU\u2010CONICET, Clinics Hospital, Jos\u00e9 de San Mart\u00edn University of Buenos Aires (UBA) Buenos Aires Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana","family":"Salaverry","sequence":"additional","affiliation":[{"name":"Laboratory of Reproductive Immunology (LAIR), IDEHU\u2010CONICET, Faculty of Pharmacy and Biochemistry UBA Buenos Aires Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estela","family":"Rey\u2010Rold\u00e1n","sequence":"additional","affiliation":[{"name":"Laboratory of Reproductive Immunology (LAIR), IDEHU\u2010CONICET, Faculty of Pharmacy and Biochemistry UBA Buenos Aires 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