Macroautophagy, often referred to as autophagy, designates the process by which portions of the cytoplasm, intracellular organelles and long-lived proteins are engulfed in double-membraned vacuoles (autophagosomes) and sent for lysosomal degradation. Basal levels of autophagy contribute to the maintenance of intracellular homoeostasis by ensuring the turnover of supernumerary, aged and/or damaged components. Under conditions of starvation, the autophagic pathway operates to supply cells with metabolic substrates, and hence represents an important pro-survival mechanism. Moreover, autophagy is required for normal development and for the protective response to intracellular pathogens. Conversely, uncontrolled autophagy is associated with a particular type of cell death (termed autophagic, or type II) that is characterized by the massive accumulation of autophagosomes. Regulators of apoptosis (e.g. Bcl-2 family members) also modulate autophagy, suggesting an intimate cross-talk between these two degradative pathways. It is still unclear whether autophagic vacuolization has a causative role in cell death or whether it represents the ultimate attempt of cells to cope with lethal stress. For a multicellular organism, autophagic cell death might well represent a pro-survival mechanism, by providing metabolic supplies during whole-body nutrient deprivation. Alternatively, type II cell death might contribute to the disposal of cell corpses when heterophagy is deficient. Here, we briefly review the roles of autophagy in cell death and its avoidance.

Introduction

The term autophagy (i.e. self-eating, from the Greek words auto=self and phagein=to eat) comprises a number of multiple intracellular processes, including CMA (chaperone-mediated autophagy), micro- and macro-autophagy, which converge on a common degradation phase mediated by lysosomes [1,2]. During CMA, cytosolic proteins containing a specific pentapeptide domain (consensus sequence=KFERQ) are unfolded and directly translocated across the lysosomal membrane [3]. On the contrary, a sequestering membrane is implicated in both micro- and macro-autophagy, yet only in the latter the engulfing apparatus is accounted for by an organelle distinct from lysosomes, known as AV (autophagic vacuole) or autophagosome [4]. For the sake of brevity, macroautophagy will be referred to as autophagy here.

During autophagy, portions of the cytoplasm (including organelles) are sequestered by a membrane of still unidentified origin (the so-called phagophore or isolation membrane), which progressively enwraps the components targeted for degradation and eventually forms a double-membraned AV. At this stage, AV-Is (early AVs) contain prominently undegraded components. Upon fusion with lysosomes, lysosomal acidic hydrolases enter the AV lumen and degrade its content. These vesicles, known as AV-IIs (late AVs), are delimited by a single membrane and surround an electron-dense content. Finally, the macromolecules generated by autophagy are released into the cytosol and can re-enter metabolic reactions [5].

Autophagy has been implicated in a broad range of pathophysiological conditions (Table 1) [6]. First, it represents a prominent mechanism of cellular adaptation to stress, such as increased temperature, high population density and nutrient deprivation. Under carbon and nitrogen starvation, for instance, the activity of the mTOR (mammalian target of rapamycin; the major negative regulator of autophagy) is rapidly shut down, and the ensuing up-regulation of the autophagic pathway supplies cells with metabolic substrates to meet their bioenergetic demands [1]. Secondly, autophagy is activated in response to invasion by intracellular pathogens [7] and plays a multifaceted role in innate and adaptive immunity, by promoting the degradation of invading microbes (xenophagy), by delivering viral nucleic acids to TLRs (Toll-like receptors), by contributing to the phagocytic pathway, and by feeding antigens to MHC class II compartments [810]. Thirdly, autophagy is implicated in several scenarios of stress-induced differentiation and normal development [6]. Thus atg (autophagy-related) genes (which encode proteins required in the various phases of the autophagic pathway [5]) are necessary for specific developmental programmes that are activated as a response to stress in the yeast Saccharomyces cerevisiae, the soil amoeba Dictyostelium discoideum and the nematode Caenorhabditis elegans [6]. In more physiological settings, the mutation of atg genes has been shown to impair the development of C. elegans, the fruitfly Drosophila melanogaster, mammalian organisms and plants [6]. Fourthly, autophagy is related to aging [11]. In this context, an enhanced turnover of old and potentially dangerous organelles (e.g. mitochondria [12]) and/or cytoplasmic structures (e.g. protein aggregates) might explain the anti-aging effects induced by fasting or dietary restrictions in C. elegans [13,14]. Alternatively, since autophagy has a major role in maintaining genomic stability, it may delay aging by avoiding the long-term effects of DNA damage [15]. Last but not least, autophagy may favour tumorigenesis, for instance by supporting the growth of cancer cells under conditions of nutrient and oxygen shortage [16]. Moreover, the essential modulator of autophagy Bec-1 (Beclin 1) is a haploinsufficient tumour suppressor, which lends further support for a profound link between autophagy and cancer [15].

Table 1
Examples of the multiple pathophysiological implications of autophagy
Setting Role(s) of autophagy Reference 
Nutrient starvation In multiple organisms, it maintains viability under conditions of carbon and nitrogen deprivation by degrading intracellular components [1
Physiological development in mammals Determines the involution of mammary glands during the lactation cycle [6,40
 Accounts for the degeneration of Mullerian and Wolffian ducts  
 Involved in the regression of the corpus luteum  
Innate and adaptive immunity Promotes the degradation of intracellular pathogens (xenophagy) [7,9,41
 Delivers endogenous antigens to MHC-class-II-loading compartments  
 Directs viral nucleic acids to TLRs (Toll-like receptors)  
 Contributes to T-cell homoeostasis  
Aging Contributes to the maintenance of genomic stability [11,13
 Ensures the turnover of old and potentially dangerous organelles/cytoplasmic structures  
Tumorigenesis Bec-1 is a haploinsufficient tumour suppressor [15,16,42
 Supports the growth of cancer cells under conditions of nutrient and oxygen shortage  
Plant immunity and development plants The plant orthologue of Bec-1 restricts the hypersensitive response to infections [43,44
 Implicated in vacuole formation and deposition of seed storage proteins  
Development of lower organisms Contributes to the degradation of salivary glands in D. melanogaster larvae [31,45
 Involved in the shaping of C. elegans nervous system  
Stress-induced differentiation Required for dauer larvae formation in C. elegans [38,46,47
 S. cerevisiae mutants in atg genes fail to undergo starvation-induced sporulation  
 Participates in the multicellular development of D. discoideum  
Setting Role(s) of autophagy Reference 
Nutrient starvation In multiple organisms, it maintains viability under conditions of carbon and nitrogen deprivation by degrading intracellular components [1
Physiological development in mammals Determines the involution of mammary glands during the lactation cycle [6,40
 Accounts for the degeneration of Mullerian and Wolffian ducts  
 Involved in the regression of the corpus luteum  
Innate and adaptive immunity Promotes the degradation of intracellular pathogens (xenophagy) [7,9,41
 Delivers endogenous antigens to MHC-class-II-loading compartments  
 Directs viral nucleic acids to TLRs (Toll-like receptors)  
 Contributes to T-cell homoeostasis  
Aging Contributes to the maintenance of genomic stability [11,13
 Ensures the turnover of old and potentially dangerous organelles/cytoplasmic structures  
Tumorigenesis Bec-1 is a haploinsufficient tumour suppressor [15,16,42
 Supports the growth of cancer cells under conditions of nutrient and oxygen shortage  
Plant immunity and development plants The plant orthologue of Bec-1 restricts the hypersensitive response to infections [43,44
 Implicated in vacuole formation and deposition of seed storage proteins  
Development of lower organisms Contributes to the degradation of salivary glands in D. melanogaster larvae [31,45
 Involved in the shaping of C. elegans nervous system  
Stress-induced differentiation Required for dauer larvae formation in C. elegans [38,46,47
 S. cerevisiae mutants in atg genes fail to undergo starvation-induced sporulation  
 Participates in the multicellular development of D. discoideum  

Autophagic cell death or life?

In multiple experimental paradigms, autophagy has been associated with a particular mode of cell death that is characterized by the massive accumulation of cytoplasmic AVs. To distinguish it from apoptosis (type I cell death), this has been termed autophagic or type II cell death. [17,18]. Although these pathways exhibit rather distinctive morphological features, it is still a matter of debate whether autophagy truly accounts for an independent cell death mode, or whether autophagic vacuolization represents a fruitless attempt of cells to adapt before succumbing to overwhelming stress (Figure 1) [1]. To discriminate between these two possibilities, it has been assumed that the inhibition of autophagy via pharmacological modulators and/or RNAi (RNA interference) would enhance long-term cell survival only when autophagy is the cause of cell death, rather than an accompanying stress response or a mere withstander phenomenon [18]. However, the inhibition of autophagy often shifts the appearance of cell death to another morphology (e.g. apoptotic and necrotic), instead of effectively improving cell survival. On one hand, this suggests that the machineries for apoptosis, autophagy and necrosis (type III cell death) are interconnected and somehow co-ordinated among each other. On the other hand, it represents another argument against the hypothesis that autophagy is a true cell-killing mechanism [1].

Roles of autophagy in cell death and survival

Figure 1
Roles of autophagy in cell death and survival

Under conditions of stress, multiple intracellular signalling pathways are initiated and may commit cells to death or lead to the activation of pro-survival mechanisms, including autophagy. If such responses succeed in re-establishing homoeostasis, cells will endure the stressful stimulus and survive. When vital mechanisms fail to counterbalance stress, cell death will occur in spite of the desperate attempt of cells to escape their fate.

Figure 1
Roles of autophagy in cell death and survival

Under conditions of stress, multiple intracellular signalling pathways are initiated and may commit cells to death or lead to the activation of pro-survival mechanisms, including autophagy. If such responses succeed in re-establishing homoeostasis, cells will endure the stressful stimulus and survive. When vital mechanisms fail to counterbalance stress, cell death will occur in spite of the desperate attempt of cells to escape their fate.

Many experimental observations have been interpreted in favour of the existence of autophagic cell death (Table 2). MEFs (mouse embryonic fibroblasts) lacking the pro-apoptotic Bcl-2 family proteins Bax and Bak fail to exhibit classical apoptosis [19] after exposure to cytotoxic agents, yet are capable of dying with a type II morphology. This death is suppressed by the down-regulation of either Atg5 or Atg6/Bec-1 [20]. Upon caspase 8 inhibition, murine L929 fibrosarcoma cells undergo extensive autophagic vacuolization and eventually die in an Atg7- and Atg6/Bec-1-dependent fashion [21]. Notably, caspase 8 is the most prominent apical caspase of the extrinsic apoptotic pathway [22], and is activated at the plasma membrane within a supramolecular complex [the so-called DISC (death-inducing signalling complex)] assembled upon the oligomerization of death receptors [23]. Among the DISC constituents, RIP1 (receptor-interacting protein 1) is required for the autophagic response induced by caspase 8 inhibition [24,25], and hence might represent a master regulator of the switch between apoptosis and non-apoptotic cell death phenotypes [26]. In HeLa carcinoma cells, RNAi-mediated down-regulation of Atg5 has been shown to inhibit autophagic vacuolization and cell death after treatment with IFN-γ (interferon-γ). Interestingly, Atg5 interacts with FADD (Fas-associated death domain), another component of the DISC, and FADD-deficient cells are protected from cell death, yet continue to manifest massive vacuolization following IFN-γ administration [27]. Recently, it has been demonstrated that autophagy is induced early during necrotic cell death in C. elegans, and that its impairment by pharmacological or genetic means actually suppresses necrosis [28]. In bax−/−/bak−/− MEFs (which are unable to activate apoptosis in response to multiple stimuli), autophagy seems to be required for the induction of cell death with necrotic features by ER (endoplasmic reticulum) stressors [29]. At a specific period of larval development, D. melanogaster salivary glands are destroyed by the concomitant activation of autophagy and caspases [30], both of which are required for proper degradation of these organs [31]. However, caspase-independent processes have been shown to take over if autophagy is experimentally up-regulated (for instance by Atg1 overexpression) [31]. Altogether, these observations reinforce the idea that autophagy represents a causal element of cell demise, either by accounting for type II cell death itself, or by contributing to (at least partially) non-autophagic lethal routines [32].

Table 2
Experimental evidence in favour or against the existence of a bona fide autophagic pathway for cell death
(a) Evidence supporting the existence of autophagic cell death 
Organism/model Genes Observations Reference 
C. elegans unc-51 (atg1Genetic ablation of the C. elegans atg1 orthologue unc-51 and pharmacological inhibition of autophagy with 3-MA reduce necrotic cell death provoked by the neurotoxic alleles deg-3(d) and mec-4(d) [28
D. melanogaster atg1 atg2 atg3 atg6 atg7 atg8 atg12 atg18 Complete salivary gland destruction is prevented by: atg2, atg3, atg8 and atg18 mutants, dominant-negative Atg1 and siRNA (small interfering RNA)-mediated down-regulation of Atg3, Atg6/Bec-1, Atg7 and Atg12. Conversely, Atg1 overexpression causes premature degradation of salivary glands [30,31
Human cervical carcinoma cells (HeLa) atg5 3-MA and Atg5 down-regulation suppresses IFNγ (interferon γ)-induced cell death and vacuole formation. Atg5 ectopic expression induces autophagic cell death [27
MEFs (mouse embryonic fibroblasts) atg5 atg6/bec-1 (beclin 1Inhibition of autophagy by pharmacological (3-MA) and genetic means (siRNA-mediated down-regulation of Atg5 and Atg6) inhibits non-apoptotic cell death of bax−/−/bak−/− cells induced by etoposide and ER (endoplasmic reticulum) stress [20,29
Murine fibrosarcoma cells (L929) atg6/bec-1 atg7 atg5 and atg6 are required for autophagic cell death induced by caspase-8 inhibition [21
(b) Evidence arguing against the existence of autophagic cell death 
Organism/model Genes Observations Reference 
Human cervical carcinoma cells (HeLa) atg5 atg6/bec-1 atg10 atg12 Silencing of atg genes or pharmacological inhibition of autophagy favours cell death under conditions of nutrient depletion [33
Human haemopoietic cells atg5 atg7 Atg5 and Atg7 depletion reduces viability of bax−/−/bak−/− cells upon growth factor (IL-3) withdrawal [35
C. elegans atg1 atg6/bec-1 atg7 atg8 atg10 Loss-of-function mutants of several atg genes impair normal dauer morphogenesis and lifespan extension [38
D. discoideum atg1 atg1 disruption induces cell death with a non-vacuolar and centrally condensed morphology [37
(a) Evidence supporting the existence of autophagic cell death 
Organism/model Genes Observations Reference 
C. elegans unc-51 (atg1Genetic ablation of the C. elegans atg1 orthologue unc-51 and pharmacological inhibition of autophagy with 3-MA reduce necrotic cell death provoked by the neurotoxic alleles deg-3(d) and mec-4(d) [28
D. melanogaster atg1 atg2 atg3 atg6 atg7 atg8 atg12 atg18 Complete salivary gland destruction is prevented by: atg2, atg3, atg8 and atg18 mutants, dominant-negative Atg1 and siRNA (small interfering RNA)-mediated down-regulation of Atg3, Atg6/Bec-1, Atg7 and Atg12. Conversely, Atg1 overexpression causes premature degradation of salivary glands [30,31
Human cervical carcinoma cells (HeLa) atg5 3-MA and Atg5 down-regulation suppresses IFNγ (interferon γ)-induced cell death and vacuole formation. Atg5 ectopic expression induces autophagic cell death [27
MEFs (mouse embryonic fibroblasts) atg5 atg6/bec-1 (beclin 1Inhibition of autophagy by pharmacological (3-MA) and genetic means (siRNA-mediated down-regulation of Atg5 and Atg6) inhibits non-apoptotic cell death of bax−/−/bak−/− cells induced by etoposide and ER (endoplasmic reticulum) stress [20,29
Murine fibrosarcoma cells (L929) atg6/bec-1 atg7 atg5 and atg6 are required for autophagic cell death induced by caspase-8 inhibition [21
(b) Evidence arguing against the existence of autophagic cell death 
Organism/model Genes Observations Reference 
Human cervical carcinoma cells (HeLa) atg5 atg6/bec-1 atg10 atg12 Silencing of atg genes or pharmacological inhibition of autophagy favours cell death under conditions of nutrient depletion [33
Human haemopoietic cells atg5 atg7 Atg5 and Atg7 depletion reduces viability of bax−/−/bak−/− cells upon growth factor (IL-3) withdrawal [35
C. elegans atg1 atg6/bec-1 atg7 atg8 atg10 Loss-of-function mutants of several atg genes impair normal dauer morphogenesis and lifespan extension [38
D. discoideum atg1 atg1 disruption induces cell death with a non-vacuolar and centrally condensed morphology [37

Conversely, multiple studies indicate that autophagy functions as a pro-survival mechanism during stress-induced cell death, and that the type II morphology results rather from the failure of cells to adapt than from the activation of a lethal pathway (Table 2) [26]. In these scenarios, pharmacological and/or genetic inhibition of autophagy accelerates the demise of cells, which then manifests with non-autophagic morphotypes. Thus cervical carcinoma cells undergoing starvation succumb to apoptosis when their autophagic machinery is blocked, and this response is reduced by caspase inhibition or Bcl-2 overexpression [33,34]. Similarly, bax−/−/bak−/− IL-3 (interleukin-3)-dependent haemopoietic cell lines utilize autophagy as a cytoprotective mechanism against IL-3 withdrawal [35]. Normally, growth factor deprivation results in the inability of cells to take up sufficient nutrients to maintain cellular bioenergetics, and rapidly triggers apoptosis. When apoptosis is impaired (as it occurs in the bax−/−/bak−/− genetic background), autophagy-proficient cells can sustain viability for several weeks (and notably remain responsive to IL-3 re-addition). Conversely, cells in which the autophagic pathway has been inhibited rapidly manifest reduced ATP levels and compromised bioenergetics and die [35]. In D. discoideum, programmed cell death with an autophagic morphology occurs after the starvation-induced production of a morphogen called DIF (differentiation-inducing factor) [36]. However, when DIF-deficient strains are deprived of nutrients, autophagy takes place independently of cell death. Conversely, the inactivation of Atg1 by homologous recombination suppresses autophagy but not cell death, which then proceeds with a non-vacuolar morphology reminiscent of necrosis [37]. Finally, autophagy is required for the developmental arrest of C. elegans known as ‘dauer diapause’, which is induced by adverse environmental conditions [38]. Nematodes carrying a mutation in the daf-2 gene exhibit a higher rate of dauer entry and an increased adult life span, both of which depend on a functional autophagic pathway [38]. Taken together, these results illustrate a crucial role for autophagy in preserving homoeostasis and preventing a premature bioenergetic catastrophe under conditions of cellular stress.

Concluding remarks

During the last decade, the question whether autophagy represents a bona fide lethal mechanism has generated great interest in the scientific community, yet remains unanswered. Although, in multiple cases, enhanced autophagy has been associated with cell death (both in vitro and in vivo), most of these reports failed to demonstrate a causal role for autophagy in initiating the lethal pathway. Moreover, these studies have often been based on the use of 3-MA (3-methyladenine), which is rather unspecific at the concentrations used for inhibiting AV formation [26]. The study of autophagy is further complicated by its complex interconnections with other cell death modalities, including apoptosis and necrosis. In most cases, suppressing one of these subroutines results in the emergence of another, with no significant improvements in the long-term survival of cells. In this context, experimental models that naturally lack the components of a specific pathway (such as D. discoideum, whose genome does not encode caspase orthologues) will be most helpful in determining the actual contribution of autophagy to cell death, and how this relates to apoptosis and necrosis.

At present, the most prominent connotation of autophagy remains that of an evolutionarily conserved pro-survival, rather than pro-death, response to stress. From this perspective, autophagic cell death could also be considered a vital mechanism that evolved from autophagy during the generation of multicellular organisms from their unicellular progenitors. As autophagy ensures the metabolic supply to starving cells by degrading intracellular components, type II cell death may contribute towards generating metabolites by sacrificing the components of multicellular organisms (i.e. cells) to sustain long-term viability under conditions of fasting. Moreover, in some tissues, autophagic cell death (instead of apoptosis) might be activated to compensate for the absence of phagocytes, by ensuring the self-disposal of cell corpses and hence avoiding the (potentially dangerous) accumulation of apoptotic bodies [39]. Autophagy looks vital, not lethal, after all.

Third Intracellular Proteolysis Meeting: A joint Biochemical Society and INPROTEOLYS Network Focused Meeting held at Auditorio de Tenerife, Santa Cruz de Tenerife, Canary Islands, Spain, 5–7 March 2008. Organized and Edited by Rosa Farràs (Centro de Investigación Príncipe Felipe, Valencia, Spain), Gemma Marfany (Barcelona, Spain), Manuel Rodríguez (CICbioGUNE, Derio, Spain), Eduardo Salido (La Laguna, Tenerife, Spain) and Dimitris Xirodimas (Dundee, U.K.).

Abbreviations

     
  • AV

    autophagic vacuole

  •  
  • AV-I

    early AV

  •  
  • AV-II

    late AV

  •  
  • atg

    gene, autophagy-related gene

  •  
  • Bec-1

    Beclin 1

  •  
  • CMA

    chaperone-mediated autophagy

  •  
  • DIF

    differentiation-inducing factor

  •  
  • DISC

    death-inducing signalling complex

  •  
  • ER

    endoplasmic reticulum

  •  
  • FADD

    Fas-associated death domain

  •  
  • IFN-γ

    interferon-γ

  •  
  • IL-3

    interleukin-3

  •  
  • 3-MA

    3-methyladenine

  •  
  • MEF

    mouse embryonic fibroblast

  •  
  • RNAi

    RNA interference

  •  
  • siRNA

    small interfering RNA

  •  
  • TLR

    Toll-like receptor

E.M. is a recipient of a DeathTrain Ph.D. student fellowship and O.K. is a recipient of an EMBO Ph.D. fellowship.

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