Search

G protein-coupled receptors (GPCRs) are the largest family of integral membrane receptors with 800 members in humans that are expressed at the cell surface responding to a large panel of extracellular stimuli. Recent advances indicate that GPCRs are also expressed in intracellular compartments where they fulfil important functions. Here, we will report on the mitochondrial localization and function of GPCRs., (© Société de Biologie, 2018.)

One of the most obvious and deleterious changes occurring with aging is a progressive loss of skeletal muscle mass and strength, a physiological process named sarcopenia. Amongst the multiple theories that have been put forward to explain sarcopenia, the mitochondrial theory of aging, which postulates that the accumulation of mitochondrial dysfunctions with aging plays a causal role in muscle atrophy, has focused intense research effort and attention in the past decades. The generally accepted view of this theory is that, due to the reactive oxygen species (ROS) production inherent to respiratory chain activity, oxidative damage to mitochondrial proteins, lipids and DNA accumulates with aging. This damage is thought to (i) exacerbate mitochondrial ROS production, (ii) impair the capacity of mitochondria to adequately match the cellular ATP demand and (iii) trigger mitochondrial-mediated apoptosis. Although very appealing, this theory remains controversial. The aims of the present review are (i) to provide the reader with a short, but comprehensive review of the current literature linking mitochondrial dysfunction and sarcopenia and (ii) to briefly discuss the potential mechanisms underlying the accumulation of mitochondrial dysfunction with muscle aging., (© 2017 médecine/sciences – Inserm.)

Mitochondria are highly dynamic organelles that provide essential metabolic functions and represent the major bioenergetic hub of eukaryotic cells. Mitochondrial dysfunctions are implicated in numerous diseases. Therefore, maintenance of a healthy pool of mitochondria is required for cellular function and survival. Mitochondrial quality control is achieved through several mechanisms that act at different levels: proteases and chaperones, the Ubiquitin-Proteasome-System (UPS) and mitophagy. Multiple mitophagy-involved programs operate independently or undergo crosstalk, and require modulated receptor activities at the outer membranes of mitochondria. In mammals, different mitophagy effectors have been characterized such as the receptors NIX, BNIP3, FUNDC1, BCL2L13, cardiolipin and the PINK1/Parkin pathway. Here we discuss the different molecular mechanisms of these mitophagy involved pathways., (© 2017 médecine/sciences – Inserm.)

The role of the mitochondrion in mammalian cell apoptosis has been established since the mid-1990s. However, the importance of this organelle in non-mammalian apoptosis has long been regarded as minor, notably because of the absence of a crucial role for cytochrome c in caspase activation. Recent results indicate that the control of caspase activation and apoptosis in Drosophila cell death occurs at the mitochondrial level. Numerous proteins that appear key for Drosophila apoptosis regulation constitutively or transiently bind to mitochondria. They participate in the cell death process at different levels such as degradation of an IAP caspase inhibitor, production of mitochondrial reactive oxygen species or stimulation of the mitochondrial fission machinery. The aim of this review is to take stock of these events that might have their counterpart in humans., (© 2016 médecine/sciences – Inserm.)

Cellular senescence is, essentially, a permanent proliferation arrest induced by various cellular stresses or inappropriate stimuli. This arrest, which is associated with dramatic changes in cell morphology, metabolism and gene expression, involves a complex signalling network aiming at stable inactivation of CDKs, major cell cycle regulators. Notably, several tumour suppressors, such as p53, pRb or p16(Ink4a), play key roles both in the initiation of the senescence program and in its maintenance, which often involves epigenetic changes. While having widely recognized roles in tumour suppression and wound healing, senescence, like the roman god Janus, recently revealed another darker face. Mostly due to altered secretion phenotype favouring inflammation, senescent cells strongly influence surrounding tissue contributing to the development of age-related pathologies, including cancer., (© 2012 médecine/sciences – Inserm / SRMS.)

Mitochondria exist as dynamic networks that often change shape and subcellular distribution. The morphology of mitochondria within a cell is controlled by precisely regulated rates of organelle fusion and fission. Several reports have described dramatic alterations in mitochondrial morphology during the early stages of apoptosis: a fragmentation of the network and the cristae remodeling. However, whether this mitochondrial fragmentation is a required step for apoptosis is highly debated. In this review the recent progress in understanding the mechanisms governing mitochondrial morphology during apoptosis and the latest advances connecting the regulation of mitochondrial morphology with apoptosis are discussed.

Mitochondria are dynamic organelles that continuously move, fuse and divide. Their overall morphology, ranging from a filamentous network to a collection of isolated dots, is determined by fusion-fission equilibrium, which depends on the cellular and physiological context. The machineries of fusion and fission, that are conserved throughout evolution, include three large GTPases of the dynamin-superfamily: Dnm1/DRP1 - involved in fission - as well as Fzo1/MFN and Mgm1/OPA1 - required for fusion. While the activities, mecanisms and regulations of mitochondrial fusion and fission machineries continue to be unravelled, the relevance of mitochondrial dynamics is witnessed by their impact on organelle functions, cell survival and cell differenciation, their requirement for embryonic development and their involvement in neurological diseases.

Ten years ago, OPA1 was identified as the major gene responsible for hereditary optic nerve degeneration, evidencing the first defect in mitochondrial network dynamics as the princeps pathophysiological mechanism in a mitochondriopathy. Later, alterations in other genes involved in mitochondrial fusion or fission, such as MFN2, DRP1 and GDAP1, were also associated with inherited neurological diseases, mainly affecting peripheral nerves. More recently, altered mitochondrial plasticity was also demonstrated in common age-related neurodegenerative disorders, as Alzheimer and Parkinson diseases, thus substantiating the critical role of mitochondrial dynamics in neurons as a key element governing the efficiency of oxidative respiration and its distribution along the axons.

Neurodegenerative diseases are more and more prevalent in our aging societies. There is strong evidence that glycogen synthase kinase (GSK)-3b plays a crucial role in Alzheimer's disease (AD). Indeed, it is involved in the regulation of the two major neuropathological hallmarks present in the brains of AD patients. Interestingly, the kinase has been implicated in multiple cellular processes and linked with the pathogenesis and neuronal loss in several neurodegenerative diseases, including Parkinson's and Huntington's diseases, in which abnormally elevated levels of GSK-3b activity have been reported. In this review, we will provide an overview of the current data pointing out the convergent role of GSK-3b in the neuropathological pathways of these diseases. We will also discuss the rationale for the development of specific inhibitors with therapeutic potentials for such devastating human diseases.

Deglycobleomycin (DBLM), the aglycon of the glycopeptide antitumor drug bleomycin (BLM), was first used since 1980 during comparative studies between BLM and DBLM in order to elucidate the role of the sugar component in the mechanism of action of BLM. In fact, the deglycosylation of BLM reduce the toxicity of this molecule and fails to produce reactive oxygen species, responsible for pulmonary fibrosis, and for anti-neoplastic activity of BLM. This causes toxic DNA lesions and ultimately leads to cell death. The therapeutic use of BLM is limited by a dose-dependent lung toxicity that eventually leads to fibrosis. Testing BLM-derivative molecules and defining their molecular mechanisms involved in tumor cell death may help to design new therapeutic approach with limited toxicity profile while maintaining anti-tumoral properties. The present review was undertaken to determine the effect of carbohydrate moiety in the mechanism of BLM induced cytotoxicity behind a comparative studies between BLM and DBLM.

Chronic renal disease is a state of microinflammation and insulin resistance. They both impact on the patient's outcome with an increased cardiovascular morbi-mortality and malnutrition. Current evidence suggests that there is a link between these two abnormal conditions. Recent data show a multiple organ regulatory pathway with a key role of bone, adipose tissue, immune system and central nervous system in energy balance control and glucose homeostasis. Thus, in searching for effective therapies, we should use an integrated approach aimed at modifying integrated outcomes rather than targeting single molecules., (2010 Elsevier Masson SAS. All rights reserved.)

Post-translational protein modifications play essential roles in many aspects of cellular functions and therefore in the maintenance of cell integrity. These protein modifications are involved at all stages of neuronal communication within the central nervous system. Sumoylation is a reversible post-translational protein modification that consists in the covalent labelling of a small protein called SUMO to lysine residues of selected target proteins. Sumoylation is a well characterized regulator of nuclear functions and has recently emerged as a key factor for numerous extranuclear processes. Furthermore, sumoylation has recently been shown to modulate synaptic transmission and is also implicated in a wide range of neurodegenerative diseases.

Since several decades anti-oxidants have been much studied, and scientists have tried to prove the preventive and curative effects in many chronic diseases. However, it is not uncommon to find highly contradictory clinical results, which may explain that consumers are less enthusiastic for anti-oxidants food supplements. First of all, definitions should be reviewed, such as that of free radicals (FR); all of them are not toxic. Some of them, such as nitric oxide, are necessary for the proper physiological functioning of the body, and eliminating them would be a mistake! However, other reactive oxygen species (ROS), which are not FR, are toxic, such as hydrogen peroxide. We have also redefined the oxidative stress, which it is not only the result of an imbalance between oxidants and anti-oxidants, but also the consequence of imbalance in the cellular redox status. The mechanisms of action, bioavailability, synergy and methods to determine the level of anti-oxidants are very sensitive topics, and it is crucial to study them if we want to obtain reliable clinical studies. Given the failure of clinical studies about anti-oxidant, we try to explain strategies which should be followed. First of all, the nature of the anti-oxidant is important; and an anti-oxidant from a natural origin must be preferred. Then, we proposed that the dose-effect was certainly responsible for the failure of tests. Indeed, doses administered in the studies was either too weak to obtain significant results, or too high, becoming pro-oxidative and eliminating the basal concentration of ROS (physiological role). Involvement of mitochondria and glycation are particularly discussed. Nutrigenomics and nutrigenetics are also discussed, which study the interactions between genetics and nutrition. Genetic polymorphism can explain the variable absorption of micronutrients. This concept leads to a truth believed by all scientists, namely the need to provide the right anti-oxidant, in adequate quantity, at the right place, at the right time and for a particular individual. To increase the anti-oxidant capacity of the body, the exogenous intake of anti-oxidants must be increased or the endogenous synthesis of anti-oxidants (SOD, GPX, GSH) must be stimulated. Targeting mitochondria and increasing their overall anti-oxidant defence system will be a challenge. Increasing the bioavailability of anti-oxidants and studying their passage through the blood-brain barrier must be also taken in consideration.

Bleomycins are a family of glycopeptides isolated from streptomyces verticillus and exhibiting antibiotic properties. They are commonly included in chemotherapy regimens used to treat patients with Hodgkin's or non Hodgkin's malignant lymphoma, squamous-cell carcinoma or germ-cell tumor. The chemical structure and action mode of bleomycin have been extensively studied, in contrast, the molecular mechanisms of the cytotoxic effects of bleomycin, in vivo, remain poorly understood. Recently, the apoptotics signaling pathway induce by bleomycin was the object of study, of many groups. In this sense, some studies suggested that bleomycin induce in some cells different apoptotic pathway in dose and time depending manner. The sensibility or the resistance to apoptosis induced by bleomycin may explain the sensibility or the resistance of tumor cells to bleomycin. The aim of this review was to describe the machinery of apoptosis induced by bleomycin in tumor cells.

The metabolic syndrome is a cluster of metabolic risk factors including: atherogenic dyslipidemia, elevated blood pressure, high plasma glucose and a prothrombotic and proinflammatory state, frequently associated to overweight. Impaired cell metabolism has been suggested as a relevant pathophysiological process. Indeed, the accumulation of intracellular fatty acylCoA and diacylglycerol, which then activate critical signal transduction pathways that ultimatly lead to suppression of insulin signalisation. Therefore a defect in mitochondrial function may be responsible for insulin resistance. Moreover, mitochondrial dysfunction has been found to take place in organs such as skeletal muscle, liver, pancreas and smoth vascular cells suggesting that mitochondrial defect could play a critical role in the occurence of cardiovascular diseases.

Neurodegenerative diseases are more and more prevalent in our aging societies. A rapid overview of the etiology of many neurodegenerative diseases like Alzheimer, Parkinson, Huntington disease and amyotrophic lateral sclerosis suggests a tight link with mitochondrial dysfunction. Since it has been recently demonstrated that activation of the SIRT1/PGC-1 pathway, in a metabolic context promotes mitochondrial function, we performed a detailed literature review on the implication of this pathway in neurodegeneration. Interestingly, transgenic mice with impaired PGC-1 expression have neurodegenerative lesions and show behavioural abnormalities. As evidenced from independent investigations, enhanced SIRT1 activity has been demonstrated to protect against axonal degeneration and to decrease the accumulation of amyloid beta peptides, the hallmark of Alzheimer disease, in cultured murine embryonic neurons. In addition, several studies suggest that resveratrol, a specific activator of SIRT1, could have protective effects in animal models of neurodegenerative diseases. Taken together, these results strongly suggest that the modulation of the SIRT1/PGC-1 pathway, which has not been well documented in the central nervous system, could become the cornerstone for new therapeutical approaches to combat neurodegeneration.

Mitochondrial disorders can not be ignored anymore in most medical areas. They include specific and widespread organ involvement, with tissue degeneration or tumor formation, being the target of numerous viruses, e.g. the HIV. Primary or secondary actors, mitochondrial dysfunctions are also supposedly playing a role in the ageing process. Despite the progresses made in the identification of their molecular bases, nearly all remains to be done as regards therapy. Research dealing with mitochondrial physiology and pathology has a long history in France and is thus not a surprise if four French teams, coming from these fundamental domains, are involved in the challenge to find ways to fight these diseases. The directions described are working tracks which promise to be long and full of pitfalls. Being original, they share a part of risk and uncertainty, but they are also with great potential with high stakes if considering the impact of these diseases.

Mitochondria play a primary role in cellular energetic metabolism, homeostasis and death. In spermatozoa, in particular, mitochondria produce the ATP necessary for motility. Mitochondrial functions depend, at least partially, on mitochondrial DNA (mtDNA). The mitochondrial genome, the transmission of which is exclusively maternal contributes to cytoplasmic heredity. Qualitative and quantitative mtDNA abnormalities have been associated with male infertility. This review focuses on the role of mtDNA in human fertility.

A number of theories have attempted to account for ageing processes in various species. Following the << rate of living >> theory of Pearl, Harman suggested fifty years ago that the accumulation of oxidants could explain the alteration of physical and cognitive functions with ageing. Oxygen metabolism leads to reactive species, including free radicals, which tend to oxidize surrounding molecules such as DNA, proteins and lipids. As a consequence various functions of cells and tissues can be altered, leading to DNA instability, protein denaturation and accumulation of lipid byproducts. Oxidative stress is an adaptive process which is triggered upon oxidant accumulation and which comprises the induction of protective and survival functions. Experimental evidence suggests that the ageing organism is in a state of oxidative stress, which supports the free radical theory. A number of other theories have been proposed ; some of these are actually compatible with the free radical theory. Caloric restriction is among the best models to increase life span in many species. While the relationship between caloric restriction and corrected metabolic rate is controversial, the decrease in ROS production by mitochondria appears to be experimentally supported. The ROS and mitochondrial theories of ageing appear to be compatible. Genetic models of increased life span, particularly those affecting the Foxo pathway, are usually accompanied by an increased resistance to oxidative insult. The free radical theory is not consistent with programmed senescence theories involving the cell division dependent decrease in telomere length ; however, oxidants are known to alter telomere structure. An appealing view of the role of oxidative stress in ageing is the trade-off principle which states that a phenotypic trait can be evolutionarily conserved because of its positive effects on development, growth or fertility, and despite its negative effect on somatic functions and ageing. It is likely that most cellular stresses which comprise adaptive and toxic functions follow such a rule.

Over the last 2 decades, the role of apoptosis in anticancer agent cytotoxicity has become clear. Defects in the regulation of apoptosis (programmed cell death) make important contributions to the pathogenesis and progression of most cancers and leukemias. Apoptosis defects also have a key role in cell resistance to chemotherapy. Mitochondria play a central part in cell death in response to anticancer agents. Most of these agents target mitochondria via caspases or other regulator elements of the apoptotic machinery. Nevertheless, some anticancer agents, already in clinical use (paclitaxel, vinblastine, lonidamine, etoposide, arsenic trioxide) or in pre-clinical development (betulinic acid, MT21), directly target and permeabilize mitochondria. The acknowledgement of mitochondria as a new target for anticancer agents provides a new way to bypass cancer cell chemoresistance.

Literature on reactive oxygen species (ROS) effects on cell biology and physiopathology is huge and appears to be controversial. This could be explained by the fact that very few studies take into account the real subcellular source of ROS production, their chemical nature and the intensity of their production. In spite of the importance of the other sites of ROS production in the cell, we decided to focus on mitochondrial ROS. Besides their key role in bioenergetics and ATP synthesis, mitochondria are one of the main sites of ROS generation within the cell. 80 % of intracellular superoxide anion is provided by the mitochondrial respiratory chain. Mitochondrial ROS production is closely associated with activity of the respiratory chain and is modulated by environmental factors which can induce constraints on respiratory chain components. Nutrient availability as well as oxygen pressure can both modulate mitochondrial ROS production. When moderately produced, ROS specifically regulate intracellular signalling pathways by reversible oxidation of proteins such as transcription factors or proteins kinases. In this way, they can trigger cell adaptation to environmental changes as modifications of energetic metabolism or hypoxia. Indeed, we demonstrated that mitochondrial ROS act as key elements in the control of white adipose tissue development by specific up-regulation of the anti-adipogenic transcription factor CHOP-10/GADD153. However, when they are produced at high level and in a chronic manner, mitochondrial ROS can also have deleterious effects by massive and irreversible oxidation of their principals targets i.e. lipids, DNA and proteins. In these conditions, mitochondrial ROS are involved in aging process and in pathological situations as metabolic disease.

Mitochondria are involved in many apoptotic responses. Following permeabilization of their outer membrane, they release many apoptogenic proteins, including cytochrome c, which contribute to caspase activation. The mechanisms responsible for membrane permeability are not completely understood. Here, we briefly review the mechanisms that have been proposed to explain this phenomenon.

Macroautophagy hereafter referred to as autophagy is a major lysosomal catabolic pathway for macromolecules and organelles conserved in eukaryotic cells. The discovery of the molecular basis of autophagy has uncovered its importance during development, life extension and in pathologies such as cancer, certain forms of myopathies and neurodegenerative diseases. Autophagy is a cell survival mechanism during starvation that is controlled by amino acids. Starvation-induced autophagy is an anti-apoptotic mechanism. However autophagy is also an alternative to apoptosis through autophagic cell death. In many situations apoptosis and autophagy can both contribute to cell dismantlement.

Mitochondria are essential organelles that are involved in numerous metabolic pathways and produce the major part of intracellular ATP by oxidative phosphorylation. Their ultrastructure was solved in the 1950s by electron microscopic analysis of ultrathin sections. Based on these pioneering studies and on the endosymbiotic origin of mitochondria, cells are often assumed to contain numerous independent mitochondria with a size similar to that of bacteria. However, electron microscopy of thick sections reveals that mitochondria form elongated and branched filaments. Optical microscopy of living cells demonstrates that mitochondrial filaments continuously modify their position and morphology and that they undergo frequent fission and fusion reactions. In this review, we revise the actual knowledge on the ultrastructure, the organization and the dynamics of the mitochondrial compartment. We review recent findings showing that mitochondria exchange molecules by fusion and we present the main proteins involved in mitochondrial fusion and fission reactions. Finally, we discuss the functional and physiological relevance of mitochondrial dynamics.

Huntington's disease is an hereditary dominant neurodegenerative disorder clinically characterised by progressive dyskinesia, cognitive decline and psychiatric disturbances. One decade after the identification of the gene whose mutation is responsible for the disease, this pathology remains incurable. However, major insights into early cellular and molecular basis of Huntington's disease have arisen from transgenic models. Transcriptional dysregulation, abnormal degradation of misfolded proteins as well as excitotoxic processes and mitochondrial dysfunction are involved in Huntington's disease. The present review discusses the recent insights gained from mouse and Drosophila models towards the understanding of pathogenesis and the development of new therapeutic tools.

Apoptotic cell death is a natural event necessary to shaping the developing nervous system and is a feature of neurodegenerative disease pathology. Subtle interactions between pro- and anti-apoptotic molecules are controlled by environmental factors such as trophic factors. The mitochondrion is a major component regulating these interactions. At the time of apoptosis, proteases, called caspases, are activated to ensure cell breakdown. In living cells, intracellular components ensure the inhibition of caspases. As such, caspases are therapeutic targets to induce or to prevent apoptosis.

Apoptosis is an essential physiological process that plays a critical role in development and cellular homeoastasis. This process is tightly regulated through multiple independent signalling pathways. Defects in apoptosis may contribute both to tumorigenesis and drug resistance. Understanding the molecular events that contribute to apoptosis enable a more rational approach to anticancer strategy development. These strategies will allow not only the development of new molecules targeting recently elucidated apoptotic signalling pathways, but also a better use of already kown drugs through new associations in so far as these target distinct signalling pathways.

The pathogenesis of type 2 diabetes is complex, with two distinct mechanisms: insulin resistance (decrease of insulin action on peripheral tissues) and insulin deficiency (impaired insulin secretion by pancreatic beta-cells). These abnormalities are due to genetic and environmental factors. Type 2 diabetes is a heterogeneous disease: besides the common form with obesity, monogenic forms (such as MODY) exist. Knowledge of these forms has permit a better understanding of the genetic factors involved in diabetes, and of their relationship with insulin resistance. In this review, we discuss the main data available on genetics of type 2 diabetes, as well as the various research approaches. Today, the genetic determinism of functional abnormalities of pancreatic beta-cell is no longer discussed. However, it is also clearly established that acquired metabolic factors may contribute to pancreatic beta-cell failure. Hyperglycaemia, even moderate, induces a reduced insulin biosynthesis potential (glucotoxicity), and the increased free fatty acid flux accelerates pancreatic beta-cell apoptosis (lipotoxicity). The role of these metabolic abnormalities in the development of type 2 diabetes is briefly described.

Determining the mode of action of different antimalarial drugs at the cellular level is essential to optimizing their use and to understanding the mechanisms underlying plasmodial resistance. The main targets for antimalarial drugs in Plasmodium falciparum have been the food vacuole and mitochondrial system. A new target is recently discovered organelle named the apicoplast. The apicoplast is the site of a number of metabolic pathways crucial to the survival of the parasite. It may also be involved in DNA replication and transcription. Antimalarial drugs are classified into three groups according to site of action, i.e., drugs that act on the food vacuole, drugs that block metabolic synthesis and oxidative processes, and drugs that interfere with membrane processes. Knowledge of these sites of action has enabled identification of new drugs with the most promising potential for development. Current antimalarial strategies prioritize combination therapies such as atovaquone/proguanil or artemether/lumefantrine and prolonged treatments to limit the risk of inducing drug resistant Plasmodium.

NO displays both pro- and anti-apoptotic properties. The parameters governing these effects begin to be elucidated. Among these figure the nature of the cells, their redox state, the flow and concentration of NO, its possibility to react with superoxide generated at the level of mitochondria. The targets of NO include molecules involved in DNA repair, such as PARP, the DNA-dependent protein kinase (DNA-PK) and p53 which control the transcription of various genes involved in the apoptotic process (bax, cdk inhibitors), and the proteasome which control the degradation of several apoptotic proteins. The inhibition by NO of caspases through S-nitrosylation of their active sites provides a rationale for our understanding of the anti-apoptotic effect of NO, but other mechanisms are involved, such as a regulation of the mitochondrial permeability. A better knowledge of the various steps of the apoptotic process that are affected by NO would allow the design of new pharmacological tools.

Until about a decade ago, few researchers in clinical or evolutionary biology paid much attention to mitochondria. But over the years, as technological advances in molecular biology made nuclear functions more accessible to them, interest in mitochondria began to revive. First, geneticists started tracing certain rare inherited disorders to mutations in the mitochondria's circular genome. More recently, other researchers have speculated that mitochondria might contribute to aging, either by releasing tissue-damaging reactive oxygen molecules or by impairing and depriving the cell of the energy it needs to function. One the most important recent developments has been the recognition that mitochondria play a central role in the regulation of programmed cell death, or apoptosis. Now, we know that mitochondria play a decisive role in life-death decisions for the cell and may choose between the apoptotic and necrotic pathways. Mitochondria can trigger cell death in a number of ways: by disrupting electron transport and energy metabolism, by activating the mitochondrial permeability transition, by releasing and/or activating proteins that mediate apoptosis. Any or all of these mechanisms may help to explain how mitochondrial defects contribute to the pathogenesis of neuronal death or dysfunction in ischemia/reperfusion injury as well as in human degenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease. This has opened up new avenues for understanding the pathogenesis of neurodegeneration and may lead to new and more effective therapeutic approaches to these diseases.

Apoptosis is a normal process occurring during development and in various tissues in humans. It appears that the mechanisms responsible for apoptosis are implicated in many aspects of human diseases. The apoptotic answer is in fact the integration of multiple different and complex signalization pathways which communicate, bifurcate and self-regulate. The mitochondria take an essential place in the description of programmed cell death and its regulation mechanisms. Caspases are the effector of apoptotic cell death. The methods of identification of the apoptosis pathways are: morphological modifications observed in microscopy, the evaluation of the difference of the mitochondrial membrane potential, the measurement of the DEVDase activity, the labelling of the phosphatidylserines by the annexin V on the cell surface, and the Western blot allowing the identification of the activated caspases. Apoptosis is implicated in many pathologies. A better understanding of the mechanisms of apoptosis and tissue specificity of the caspases make it possible to consider in the future the development of synthetic inhibitors as serious candidates for a therapeutic intervention.

Using an experimental model of anoxia-reoxygenation applied to suspensions of mitochondria isolated from rat cortex, we have searched the effects of resveratrol added to the suspension or previously injected to rats from which mitochondria were extracted. With this model, we observe that resveratrol counteracts decoupling effects induced by anoxia-reoxygenation. It also fully inhibits intermembrane cytochrome c release, initial step of mitochondrial apoptosis and blocks ATP generation which achieves it. These effects are concentration-dependent and take place at low concentrations. It is concluded that resveratrol limits or suppresses the mitochondrial deleterious effects promoted by anoxia followed by reoxygenation.

The dysregulation of programmed cell death (apoptosis) is involved in different pathologies including cancer, which is frequently associated with an increase resistance to apoptosis induction. We discovered in 1994 the implication of a specific organelle, the mitochondrion, in apoptosis. Our result have demonstrated that mitochondrial membrane permeabilization (MMP) constitutes a decisive step of the apoptotic process. MMP is regulated by numerous effectors, including the proteins from the Bcl-2/Bax family (oncogenes or tumor suppressor genes which modulate apoptosis), which interact with sessile proteins of mitochondria. MMP can be induced by a large number of pro-apoptotic second messengers, as well as by some experimental anti-cancer agents, suggesting that MMP constitutes a point of integration of the apoptotic response. As a result of MMP, several apoptogenic proteins normally confined to mitochondria are released in the extra-mitochondrial space and participate in the suicidal dismantling of the cell. We have identified several mitochondrial apoptogenic proteins, one of which, the apoptosis inducing factor (AIF) has been cloned. AIF appears to be one of the principal effectors of the apoptotic machinery. Genetic inactivation of AIF abolishes the first wave of apoptosis indispensable for early embryonic morphogenesis. In contrast, its presence in the extra-mitochondrial compartment suffices to kill cells. Altogether, these results allow for the development of new strategies aiming at inducing apoptosis in cancer cells.