Nuclear cytochrome <i>c</i> – a mitochondrial visitor regulating damaged chromatin dynamics

Dı́az-Moreno, Irene; Velázquez‐Cruz, Alejandro; Curran‐French, Seamus; Díaz‐Quintana, Antonio; Rosa, Miguel Á. De la

doi:10.1002/1873-3468.12959

Cited by 28 publications

(24 citation statements)

References 34 publications

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“…This hypothesis states that low levels of DNA lesions would induce nuclear translocation of C c , delaying nucleosome assembly to increase the time available for DNA to be repaired. However, if DNA damage persists, more C c accumulates in the nucleus, thereby blocking DNA remodeling by sequestering the vast majority of histone chaperones . Thus, genotoxic stress triggers the DDR signaling cascade leading to the nuclear translocation of C c , which first plays a prosurvival role and then may turn into a prodeath factor.…”

Section: Nuclear Localization Is What Matters: Converting CC From a Kmentioning

confidence: 99%

“…We have recently proposed the existence of a general mechanism based on a dual role for nuclear C c under DNA damage . This hypothesis states that low levels of DNA lesions would induce nuclear translocation of C c , delaying nucleosome assembly to increase the time available for DNA to be repaired.…”

Section: Nuclear Localization Is What Matters: Converting CC From a Kmentioning

confidence: 99%

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New moonlighting functions of mitochondrial cytochrome c in the cytoplasm and nucleus

et al. 2019

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Cytochrome c (Cc) is a protein that functions as an electron carrier in the mitochondrial respiratory chain. However, Cc has moonlighting roles outside mitochondria driving the transition of apoptotic cells from life to death. When living cells are damaged, Cc escapes its natural mitochondrial environment and, once in the cytosol, it binds other proteins to form a complex named the apoptosome—a platform that triggers caspase activation and further leads to controlled cell dismantlement. Early released Cc also binds to inositol 1,4,5‐triphosphate receptors on the ER membrane, which stimulates further massive Cc release from mitochondria. Besides the well‐characterized binding proteins contributing to the proapoptotic functions of Cc, many novel protein targets have been recently described. Among them, histone chaperones were identified as key partners of Cc following DNA breaks, indicating that Cc might modulate chromatin dynamics through competitive binding to histone chaperones. In this article, we review the ample set of recently discovered antiapoptotic proteins—involved in DNA damage, transcription, and energetic metabolism—reported to interact with Cc in the cytoplasm and even the nucleus upon DNA breaks.

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Section: Nuclear Localization Is What Matters: Converting CC From a Kmentioning

confidence: 99%

Section: Nuclear Localization Is What Matters: Converting CC From a Kmentioning

confidence: 99%

New moonlighting functions of mitochondrial cytochrome c in the cytoplasm and nucleus

et al. 2019

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“…Cytc is a highly positively charged protein that promotes its interaction with lowcomplexity acidic regions of the above histone-binding chaperones. This inhibitory interaction of Cytc has been proposed to be a cellular life-or-death mechanism, depending on the severity of cell damage (44). Finally, Cytc was recently shown to have yet another catalytic function by acting as a plasmalogenase in vitro, cleaving the vinyl-ether linkage of important phospholipids called plasmalogens, which are involved in lipid signaling (45).…”

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confidence: 99%

Tissue‐specific regulation of cytochrome c by post‐translational modifications: respiration, the mitochondrial membrane potential, ROS, and apoptosis

et al. 2018

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Cytochrome c (Cytc) plays a vital role in the mitochondrial electron transport chain (ETC). In addition, it is a key regulator of apoptosis. Cytc has multiple other functions including ROS production and scavenging, cardiolipin peroxidation, and mitochondrial protein import. Cytc is tightly regulated by allosteric mechanisms, tissue‐specific isoforms, and post‐translational modifications (PTMs). Distinct residues of Cytc are modified by PTMs, primarily phosphorylations, in a highly tissue‐specific manner. These modifications downregulate mitochondrial ETC flux and adjust the mitochondrial membrane potential (ΔΨm), to minimize reactive oxygen species (ROS) production under normal conditions. In pathologic and acute stress conditions, such as ischemia–reperfusion, phosphorylations are lost, leading to maximum ETC flux, ΔΨm hyperpolarization, excessive ROS generation, and the release of Cytc. It is also the dephosphorylated form of the protein that leads to maximum caspase activation. We discuss the complex regulation of Cytc and propose that it is a central regulatory step of the mammalian ETC that can be rate limiting in normal conditions. This regulation is important because it maintains optimal intermediate ΔΨm, limiting ROS generation. We examine the role of Cytc PTMs, including phosphorylation, acetylation, methylation, nitration, nitrosylation, and sulfoxidation and consider their potential biological significance by evaluating their stoichiometry.—Kalpage, H. A., Bazylianska, V., Recanati, M. A., Fite, A., Liu, J., Wan, J., Mantena, N., Malek, M. H., Podgorski, I., Heath, E. I., Vaishnav, A., Edwards, B. F., Grossman, L. I., Sanderson, T. H., Lee, I., Hüttemann, M. Tissue‐specific regulation of cytochrome c by post‐translational modifications: respiration, the mitochondrial membrane potential, ROS, and apoptosis. FASEB J. 33, 1540–1553 (2019). http://www.fasebj.org

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“…Recent data indicate that the programmed cell death network involving C c is complex, and that C c targets several proteins that are functionally equivalent in humans and plants ( 22 – 24 ). In both type of cells, for example, C c reaches the cell nucleus upon DNA damage and sequesters human SET/TAF1β and plant NRP1 histone chaperones that remodel chromatin ( 25 – 27 ).…”

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confidence: 99%

Oxidative stress is tightly regulated by cytochrome c phosphorylation and respirasome factors in mitochondria

Guerra‐Castellano

Díaz-Quintana

Pérez‐Mejías

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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SignificanceDysfunction of mitochondria, the powerhouses of living cells, favors the onset of human diseases, namely neurodegenerative diseases, cardiovascular pathologies, and cancer. Actually, respiratory cytochrome c has been found to be phosphorylated at tyrosine 97 during the insulin-induced neuroprotection response following a brain ischemic injury. Here, we report that the decrease in neuronal death could be directly ascribed to changes in mitochondrial metabolism—including lower production of reactive oxygen species—and cell homeostasis induced by cytochrome c phosphorylation. Our findings thus provide the basis for understanding the molecular mechanism and potential use of phosphomimetic species of cytochrome c, thereby yielding new opportunities to develop more efficient therapies against acute pathologies.

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Nuclear cytochrome c – a mitochondrial visitor regulating damaged chromatin dynamics

Cited by 28 publications

References 34 publications

New moonlighting functions of mitochondrial cytochrome c in the cytoplasm and nucleus

New moonlighting functions of mitochondrial cytochrome c in the cytoplasm and nucleus

Tissue‐specific regulation of cytochrome c by post‐translational modifications: respiration, the mitochondrial membrane potential, ROS, and apoptosis

Oxidative stress is tightly regulated by cytochrome c phosphorylation and respirasome factors in mitochondria

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