Mechanisms of autophagic programmed cell death escape during the very early stages of senescent cells neoplastic evolution

La senescence est un état d’arrêt prolifératif mis en place par les cellules en réponse à différents stress (raccourcissement des télomères, stress oxydant, ou activation d’oncogènes). Bien que la sénescence soit considérée comme irréversible, nous avons récemment montré, en utilisant des kératinocytes humains normaux d’épiderme, que certaines cellules sénescentes réactivent spontanément le processus mitotique pour générer des cellules proliférantes, baptisées émergentes post-sénescence, qui sont transformées et tumorigènes en souris nude. Nous avons montré dans la première partie de ce travail que les cellules sénescentes qui ne génèrent pas de cellules émergentes meurent. La mort engagée à la sénescence n’est ni apoptotique ni nécrotique, mais implique l’élimination par macroautophagie de nombreux composés cellulaires vitaux. Nous avons ensuite démontré que le stress oxydant, via les dommages qu’il crée, notamment aux niveaux nucléaire et mitochondrial, est responsable de l’activation de la mort cellulaire programmée par macroautophagie. Les cellules sénescentes progénitrices des cellules néoplasiques génèrent quant à elle moins d’espèces réactives de l’oxygène (ROS) que le reste des cellules sénescentes, ce qui leur permet d’échapper à la mort. Cependant, pour générer les cellules émergentes, elles doivent maintenir une activité macroautophagique de ménage. L’ensemble de ces travaux démontre donc que le devenir des kératinocytes sénescents dépend de leur niveau de ROS. Un haut niveau de ROS induirait une activité macroautophagique élevée et létale, alors qu’un niveau plus bas induirait une activité trop faible pour induire la mort, mais suffisante pour éliminer les composés cellulaires oxydés. Dans cette situation, les cellules deviendraient permissives à l’évolution néoplasique si les dommages oxydants touchent l’ADN et affectent des oncogènes, suppresseurs de tumeurs, ou d’autres régulateurs fondamentaux.Senescence is a non proliferative state that occurs in response to telomere shortening, oxidative stress or oncogenic activation. Whereas senescence is generally considered as an irreversible growth arrest, we recently reported, using Normal Human Epidermal Keratinocytes (NHEKs), that few senescent cells can spontaneously reactivate a mitotic process to generate so-called post-senescence emergent cells which are transformed and able to form skin hyperplasia in nude mice. In the first part of this work, we have investigated the outcome of the majority of senescent cells that do not generate emergent cells. We highlighted that senescent cells massively die during the growth arrest. Interestingly, the death is not associated with apoptotic or necrotic features but involves the elimination of numerous vital cells components by macroautophagy. We next investigated the mechanism that activates the autophagic programmed cell death in senescent keratinocytes. We show that oxidative stress occuring during senescence causes numerous cellular damages, notably to nucleus and mitochondria, that activate the macroautophagic process to ultimately lead to the death. In the last part of this work, we have investigated the relationship between oxidative stress and macroautophagy during the generation of post-senescence emergent cells. We show that progenitors of these neoplastic cells display less reactive oxygen species (ROS) production than other senescent keratinocytes, and hence escape autophagic cell death. However, in order to generate PS emergent cells, they have to maintain an housekeeping autophagic activity. Taken together, these results indicate that the outcome of a senescent cell is driven by its ROS level. A high ROS level induces a high and lethal activation of autophagy. At a lower ROS level, the cell activates a moderated autophagy that fails to induce death but favors the elimination of oxidized proteins and organelles. By this way, this cell becomes permissive to neoplastic evolution consecutively to the putative oxidative alteration of oncogenes, tumor suppressor genes or other crucial cell regulators

Mechanisms of autophagic programmed cell death escape during the very early stages of senescent cells neoplastic evolution

La senescence est un état d’arrêt prolifératif mis en place par les cellules en réponse à différents stress (raccourcissement des télomères, stress oxydant, ou activation d’oncogènes). Bien que la sénescence soit considérée comme irréversible, nous avons récemment montré, en utilisant des kératinocytes humains normaux d’épiderme, que certaines cellules sénescentes réactivent spontanément le processus mitotique pour générer des cellules proliférantes, baptisées émergentes post-sénescence, qui sont transformées et tumorigènes en souris nude. Nous avons montré dans la première partie de ce travail que les cellules sénescentes qui ne génèrent pas de cellules émergentes meurent. La mort engagée à la sénescence n’est ni apoptotique ni nécrotique, mais implique l’élimination par macroautophagie de nombreux composés cellulaires vitaux. Nous avons ensuite démontré que le stress oxydant, via les dommages qu’il crée, notamment aux niveaux nucléaire et mitochondrial, est responsable de l’activation de la mort cellulaire programmée par macroautophagie. Les cellules sénescentes progénitrices des cellules néoplasiques génèrent quant à elle moins d’espèces réactives de l’oxygène (ROS) que le reste des cellules sénescentes, ce qui leur permet d’échapper à la mort. Cependant, pour générer les cellules émergentes, elles doivent maintenir une activité macroautophagique de ménage. L’ensemble de ces travaux démontre donc que le devenir des kératinocytes sénescents dépend de leur niveau de ROS. Un haut niveau de ROS induirait une activité macroautophagique élevée et létale, alors qu’un niveau plus bas induirait une activité trop faible pour induire la mort, mais suffisante pour éliminer les composés cellulaires oxydés. Dans cette situation, les cellules deviendraient permissives à l’évolution néoplasique si les dommages oxydants touchent l’ADN et affectent des oncogènes, suppresseurs de tumeurs, ou d’autres régulateurs fondamentaux.Senescence is a non proliferative state that occurs in response to telomere shortening, oxidative stress or oncogenic activation. Whereas senescence is generally considered as an irreversible growth arrest, we recently reported, using Normal Human Epidermal Keratinocytes (NHEKs), that few senescent cells can spontaneously reactivate a mitotic process to generate so-called post-senescence emergent cells which are transformed and able to form skin hyperplasia in nude mice. In the first part of this work, we have investigated the outcome of the majority of senescent cells that do not generate emergent cells. We highlighted that senescent cells massively die during the growth arrest. Interestingly, the death is not associated with apoptotic or necrotic features but involves the elimination of numerous vital cells components by macroautophagy. We next investigated the mechanism that activates the autophagic programmed cell death in senescent keratinocytes. We show that oxidative stress occuring during senescence causes numerous cellular damages, notably to nucleus and mitochondria, that activate the macroautophagic process to ultimately lead to the death. In the last part of this work, we have investigated the relationship between oxidative stress and macroautophagy during the generation of post-senescence emergent cells. We show that progenitors of these neoplastic cells display less reactive oxygen species (ROS) production than other senescent keratinocytes, and hence escape autophagic cell death. However, in order to generate PS emergent cells, they have to maintain an housekeeping autophagic activity. Taken together, these results indicate that the outcome of a senescent cell is driven by its ROS level. A high ROS level induces a high and lethal activation of autophagy. At a lower ROS level, the cell activates a moderated autophagy that fails to induce death but favors the elimination of oxidized proteins and organelles. By this way, this cell becomes permissive to neoplastic evolution consecutively to the putative oxidative alteration of oncogenes, tumor suppressor genes or other crucial cell regulators

Détermination des mécanismes d'échappement à la mort par autophagie lors des étapes très précoces de transformation de cellules sénescentes en cellules tumorales

La senescence est un état d arrêt prolifératif mis en place par les cellules en réponse à différents stress (raccourcissement des télomères, stress oxydant, ou activation d oncogènes). Bien que la sénescence soit considérée comme irréversible, nous avons récemment montré, en utilisant des kératinocytes humains normaux d épiderme, que certaines cellules sénescentes réactivent spontanément le processus mitotique pour générer des cellules proliférantes, baptisées émergentes post-sénescence, qui sont transformées et tumorigènes en souris nude. Nous avons montré dans la première partie de ce travail que les cellules sénescentes qui ne génèrent pas de cellules émergentes meurent. La mort engagée à la sénescence n est ni apoptotique ni nécrotique, mais implique l élimination par macroautophagie de nombreux composés cellulaires vitaux. Nous avons ensuite démontré que le stress oxydant, via les dommages qu il crée, notamment aux niveaux nucléaire et mitochondrial, est responsable de l activation de la mort cellulaire programmée par macroautophagie. Les cellules sénescentes progénitrices des cellules néoplasiques génèrent quant à elle moins d espèces réactives de l oxygène (ROS) que le reste des cellules sénescentes, ce qui leur permet d échapper à la mort. Cependant, pour générer les cellules émergentes, elles doivent maintenir une activité macroautophagique de ménage. L ensemble de ces travaux démontre donc que le devenir des kératinocytes sénescents dépend de leur niveau de ROS. Un haut niveau de ROS induirait une activité macroautophagique élevée et létale, alors qu un niveau plus bas induirait une activité trop faible pour induire la mort, mais suffisante pour éliminer les composés cellulaires oxydés. Dans cette situation, les cellules deviendraient permissives à l évolution néoplasique si les dommages oxydants touchent l ADN et affectent des oncogènes, suppresseurs de tumeurs, ou d autres régulateurs fondamentaux.Senescence is a non proliferative state that occurs in response to telomere shortening, oxidative stress or oncogenic activation. Whereas senescence is generally considered as an irreversible growth arrest, we recently reported, using Normal Human Epidermal Keratinocytes (NHEKs), that few senescent cells can spontaneously reactivate a mitotic process to generate so-called post-senescence emergent cells which are transformed and able to form skin hyperplasia in nude mice. In the first part of this work, we have investigated the outcome of the majority of senescent cells that do not generate emergent cells. We highlighted that senescent cells massively die during the growth arrest. Interestingly, the death is not associated with apoptotic or necrotic features but involves the elimination of numerous vital cells components by macroautophagy. We next investigated the mechanism that activates the autophagic programmed cell death in senescent keratinocytes. We show that oxidative stress occuring during senescence causes numerous cellular damages, notably to nucleus and mitochondria, that activate the macroautophagic process to ultimately lead to the death. In the last part of this work, we have investigated the relationship between oxidative stress and macroautophagy during the generation of post-senescence emergent cells. We show that progenitors of these neoplastic cells display less reactive oxygen species (ROS) production than other senescent keratinocytes, and hence escape autophagic cell death. However, in order to generate PS emergent cells, they have to maintain an housekeeping autophagic activity. Taken together, these results indicate that the outcome of a senescent cell is driven by its ROS level. A high ROS level induces a high and lethal activation of autophagy. At a lower ROS level, the cell activates a moderated autophagy that fails to induce death but favors the elimination of oxidized proteins and organelles. By this way, this cell becomes permissive to neoplastic evolution consecutively to the putative oxidative alteration of oncogenes, tumor suppressor genes or other crucial cell regulators.LILLE1-Bib. Electronique (590099901) / SudocSudocFranceF

Oxidative Stress in Cardiovascular Diseases

International audienceReactive oxygen species (ROS) are subcellular messengers in signal transductions pathways with both beneficial and deleterious roles. ROS are generated as a by-product of mitochondrial respiration or metabolism or by specific enzymes such as superoxide dismutases, glutathione peroxidase, catalase, peroxiredoxins, and myeloperoxidases. Under physiological conditions, the low levels of ROS production are equivalent to their detoxification, playing a major role in cellular signaling and function. In pathological situations, particularly atherosclerosis or hypertension, the release of ROS exceeds endogenous antioxidant capacity, leading to cell death. At cardiovascular levels, oxidative stress is highly implicated in myocardial infarction, ischemia/reperfusion, or heart failure. Here, we will first detail the physiological role of low ROS production in the heart and the vessels. Indeed, ROS are able to regulate multiple cardiovascular functions, such as cell proliferation, migration, and death. Second, we will investigate the implication of oxidative stress in cardiovascular diseases. Then, we will focus on ROS produced by NAPDH oxidase or during endothelial or mitochondrial dysfunction. Given the importance of oxidative stress at the cardiovascular level, antioxidant therapies could be a real benefit. In the last part of this review, we will detail the new therapeutic strategies potentially involved in cardiovascular protection and currently under study

Mitophagy Regulation Following Myocardial Infarction

International audienceMitophagy, which mediates the selective elimination of dysfunctional mitochondria, is essential for cardiac homeostasis. Mitophagy is regulated mainly by PTEN-induced putative kinase protein-1 (PINK1)/parkin pathway but also by FUN14 domain-containing 1 (FUNDC1) or Bcl2 interacting protein 3 (BNIP3) and BNIP3-like (BNIP3L/NIX) pathways. Several studies have shown that dysregulated mitophagy is involved in cardiac dysfunction induced by aging, aortic stenosis, myocardial infarction or diabetes. The cardioprotective role of mitophagy is well described, whereas excessive mitophagy could contribute to cell death and cardiac dysfunction. In this review, we summarize the mechanisms involved in the regulation of cardiac mitophagy and its role in physiological condition. We focused on cardiac mitophagy during and following myocardial infarction by highlighting the role and the regulation of PI NK1/parkin-; FUNDC1-; BNIP3- and BNIP3L/NIX-induced mitophagy during ischemia and reperfusion

Non-coding RNAs in cardiac autophagy following myocardial infarction

International audienceMacroautophagy is an evolutionarily conserved process of the lysosome-dependent degradation of damaged proteins and organelles and plays an important role in cellular homeostasis. Macroautophagy is upregulated after myocardial infarction (MI) and seems to be detrimental during reperfusion and protective during left ventricle remodeling. Identify new regulators of cardiac autophagy may help to maintain the activity of this process and protect the heart from MI effects. Recently, it was shown that non-coding RNAs (microRNAs and long non-coding RNAs) are involved on autophagy regulation in different cell types including cardiac cells. In this review, we summarized the role of macroautophagy in the heart following MI and we focused on the non-coding RNAs and their targeted genes reported to regulate autophagy in the heart under these pathological conditions

Integrative System Biology Analyses Identify Seven MicroRNAs to Predict Heart Failure

Heart failure (HF) has several etiologies including myocardial infarction (MI) and left ventricular remodeling (LVR), but its progression remains difficult to predict in clinical practice. Systems biology analyses of LVR after MI provide molecular insights into this event such as modulation of microRNA (miRNA) that could be used as a signature of HF progression. To define a miRNA signature of LVR after MI, we use 2 systems biology approaches, integrating either proteomic data generated from LV of post-MI rat induced by left coronary artery ligation or multi-omics data (proteins and non-coding RNAs) generated from plasma of post-MI patients from the REVE-2 study. The first approach predicted that 13 miRNAs and 3 of these miRNAs would be validated to be associated with LVR in vivo: miR-21-5p, miR-23a-3p and miR-222-3p. The second approach predicted that 24 miRNAs among 1310 molecules and 6 of these miRNAs would be selected to be associated with LVR in silico: miR-17-5p, miR-21-5p, miR-26b-5p, miR-222-3p, miR-335-5p and miR-375. We identified a signature of 7 microRNAs associated with LVR after MI that support the interest of integrative systems biology analyses to define a miRNA signature of HF progression