Evaluation of the Roles of Apoptosis, Autophagy, and Mitophagy in the Loss of Plating Efficiency Induced by Bax Expression in Yeast

Abstract

We found recently that, in yeast cells, the heterologous expression of Bax induces a loss of plating efficiency different from that induced by acute stress because it is associated with the maintenance of plasma membrane integrity (Camougrand, N., Grelaud-Coq, A., Marza, E., Priault, M., Bessoule, J. J., and Manon, S. (2003) Mol. Microbiol. 47, 495-506). Bax effects were neither dependent on the presence of the yeast metacaspase Yca1p and the apoptosis-inducing factor homolog nor associated with the appearance of typical apoptotic markers such as metacaspase activation, annexin V binding, and DNA cleavage. Yeast cells expressing Bax instead displayed autophagic features, including increased accumulation of Atg8p, activation of vacuolar alkaline phosphatase, and the presence of autophagosomes and autophagic bodies. However, the inactivation of autophagy did not prevent and actually slightly accelerated Bax-induced loss of plating efficiency. On the other hand, Bax expression induced a fragmentation of the mitochondrial network, which retained, however, some level of organization in wild-type cells. However, when expressed in cells inactivated for the gene UTH1, previously shown to be involved in mitophagy, Bax induced a complete disorganization of the mitochondrial network. Interestingly, although mitochondrially targeted green fluorescent protein was slowly degraded in the wild-type strain, it remained unaffected in the mutant. Furthermore, the slow loss of plating efficiency in the mutant strain correlated with a loss of plasma membrane integrity. These data suggest that Bax-induced loss of growth capacity is associated with maintenance of plasma membrane integrity dependent on UTH1, suggesting that selective degradation of altered mitochondria is required for a regulated loss of growth capacity.Recent data have provided evidence for the existence of different forms of programmed cell death. In addition to the long time established existence of apoptosis in the worm Caenorhabditis elegans (1), apoptotic markers associated with loss of viability have been observed in various organisms, including Dictyostelium discoideum (2), Leishmania sp. (3), and Saccharomyces cerevisiae (4 -7). However, apoptosis might not be the only process leading to programmed cell death. Autophagy, an intracellular degradation process normally responsible for cell survival under starvation conditions, has been observed frequently as accompanying the loss of growth capacity in mammalian cells (8 -11). Moreover, in mammalian cells, data have suggested a co-regulation of apoptosis and autophagy, which could both participate in cell death (12, 13). These observations support the occurrence of cell death associated with autophagy, although certain authors consider autophagy to be a cellular attempt to survive apoptotic cell death (10, 14 -17). The simpler eukaryotic models D. discoideum and Podospora anserina have provided the opportunity to demonstrate that autophagy inactivation stimulates rather than inhibits the kinetics of physiological ...

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