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Mitochondrial nucleoid clusters protect newly synthesized mtDNA during Doxorubicin- and Ethidium Bromide-induced mitochondrial stress

SYSNO ASEP	0462870
Druh ASEP	J - Článek v odborném periodiku
Zařazení RIV	J - Článek v odborném periodiku
Poddruh J	Článek ve WOS
Název	Mitochondrial nucleoid clusters protect newly synthesized mtDNA during Doxorubicin- and Ethidium Bromide-induced mitochondrial stress
Tvůrce(i)	Alán, Lukáš (FGU-C)_{RID, ORCID} Špaček, Tomáš (FGU-C)_{RID, ORCID} Pajuelo-Reguera, David (FGU-C)_{RID, ORCID, SAI} Jabůrek, Martin (FGU-C)_{ORCID, RID} Ježek, Petr (FGU-C)_{RID, ORCID}
Zdroj.dok.	Toxicology and Applied Pharmacology. - : Elsevier - ISSN 0041-008X Roč. 302, Jul 1 (2016), s. 31-40
Poč.str.	10 s.
Jazyk dok.	eng - angličtina
Země vyd.	US - Spojené státy americké
Klíč. slova	Doxorubicin ; Ethidium Bromide ; nucleoid clusters ; mitochondrial DNA stress ; mitochondrial transcription factor A
Vědní obor RIV	EB - Genetika a molekulární biologie
CEP	GAP305/12/1247 GA ČR - Grantová agentura ČR
	LQ1604 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy
	ED1.1.00/02.0109 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy
Institucionální podpora	FGU-C - RVO:67985823
UT WOS	000376472100004
EID SCOPUS	84964238280
DOI	10.1016/j.taap.2016.04.011
Anotace	Mitochondrial DNA (mtDNA) is compacted in ribonucleoprotein complexes called nucleoids, which can divide or move within the mitochondrial network. Mitochondrial nucleoids are able to aggregate into clusters upon reaction with intercalators such as the mtDNA depletion agent Ethidium Bromide (EB) or anticancer drug Doxorobicin (DXR). However, the exact mechanism of nucleoid clusters formation remains unknown. Resolving these processes may help to elucidate the mechanisms of DXR-induced cardiotoxicity. Therefore, we addressed the role of two key nucleoid proteins; mitochondrial transcription factor A (TFAM) and mitochondrial single-stranded binding protein (mtSSB); in the formation of mitochondrial nucleoid clusters during the action of intercalators. We found that both intercalators cause numerous aberrations due to perturbing their native status. By blocking mtDNA replication, both agents also prevented mtDNA association with TFAM, consequently causing nucleoid aggregation into large nucleoid clusters enriched with TFAM, co-existing with the normal nucleoid population. In the later stages of intercalation (> 48 h), TFAM levels were reduced to 25%. In contrast, mtSSB was released from mtDNA and freely distributed within the mitochondrial network. Nucleoid clusters mostly contained nucleoids with newly replicated mtDNA, however the nucleoid population which was not in replication mode remained outside the clusters. Moreover, the nucleoid clusters were enriched with p53, an anti-oncogenic gatekeeper. We suggest that mitochondrial nucleoid clustering is a mechanism for protecting nucleoids with newly replicated DNA against intercalators mediating genotoxic stress. These results provide new insight into the common mitochondrial response to mtDNA stress and can be implied also on DXR-induced mitochondrial cytotoxicity.
Pracoviště	Fyziologický ústav
Kontakt	Lucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400
Rok sběru	2017

Počet záznamů: 1