Macroautophagy versus mitochondrial autophagy: a question of fate?

Autophagy is a catabolic process that allows recycling of cytoplasmic components (including organelles) into basic components, offering a bioenergetically efficient alternative to de novo synthesis. In yeast, autophagy functions primarily as an adaptive mechanism allowing survival in the response to changes in the availability of nutrients in the environment. Over the past decade, genetic screens performed in yeast have elucidated many of the molecular components involved in this adaptive response.^{1, 2, 3} More recently, the roles of homologous genes are being explored in multicellular organisms and in cells derived from these organisms.⁴ These studies have demonstrated that while autophagy is often induced as part of an adaptive response, induction of autophagy may also lead to cell death. During Drosophila larval development, for example, starvation-induced autophagy occurs in the larval fat body and is required for maintaining circulating nutrient levels and survival of the larvae under unfavorable nutritional conditions;⁵ by contrast, programmed autophagy results in cell death and is the primary means of removing certain larval organs during metamorphosis.⁶ On a cellular level, autophagy is observed prior to apoptosis in growth factor-deprived neuronal cultures.^{7, 8} In cells lacking critical proapoptotic proteins, the adaptive process of autophagy aimed at maintaining bioenergetic homeostasis can be unmasked in response to growth-factor withdrawal.⁹ In contrast, cell death in response to a variety of chemicals has been suggested to result from autophagic destruction of the cell and to be suppressed by inhibition of autophagy.¹⁰ The factors that determine whether induction of autophagy contributes to cell survival or cell death are not well-elucidated; however, two key issues may be the rate of autophagic degradation and the specificity of the engulfed components. Although autophagy is generally considered a nonspecific process, there are instances where the mitochondria (and other organelles) appear to be specifically targeted. Here, we focus on the signals and pathways involved in regulating the induction of autophagy and mitochondrial autophagy in yeast and how these processes are relevant to survival and death of mammalian cells.

Under vegetative conditions, core components of the autophagic machinery are involved in the cvt pathway, which is a mechanism for targeting specific cytosolic proteins, such as the vacuolar protease aminopeptidase I (ApeI) and α-mannosidase, to the yeast vacuole.^{21, 22} The process is similar to autophagy in that it involves sequestration in double membrane vesicles (cvt vesicles) that fuse with the yeast vacuole; but differs from autophagy in the specificity of the engulfed material and the size of the vesicles ^{23, 24}(Figure 1). Although there are proteins that are specific to one pathway or the other, many components of the cvt and autophagy pathways are shared. Atg1p is one of the proteins that are required for both processes, but is unique in that through modulation of its kinase activity and its association with Atg13p, Atg1p functions as a molecular switch between the cvt and autophagy pathways (Figure 2). Although the mechanism by which Atg1p regulates the switch are not fully elucidated, there is circumferential evidence to suggest that Atg1 may be involved in regulating both the size and composition of the vesicles during cvt and autophagy. First of all, Atg1 interacts with Atg11, a protein that is required for cvt (but not autophagy) and is involved in the specific packaging of cargo through its interaction with Atg19 and Atg8.^{25, 26} It is possible that the interaction of Atg13p and Atg1p diminishes the role of Atg11 by excluding it from the complex or inhibiting the formation of Atg11 homo-dimers or -oligomers. Atg13 and Atg1 also form a complex with Atg17, which is involved in regulating the size of the vesicles during autophagy.^{27, 28} Another way that Atg1p differentially regulates the cvt and autophagy pathways is through the recycling of Atg9p and/or Atg23p (a peripheral membrane protein) depending on the kinase activity of Atg1p²⁰. Similar to Atg11, Atg23 is essential for cvt.²⁹ The regulation of Atg1 by Tor and some of the differences between the complexes formed during autophagy and cvt are depicted in Figure 2. Although there is no direct mammalian correlate of the cvt pathway, the observation that the mammalian and Caenorhabdhitis elegans Atg1 homologues may be involved in the trafficking of neuronal receptors during axonal growth suggests that this primitive pathway may have been adapted for cell-type-specific functions in multicellular organisms.^{30, 31, 32}

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