Role of mitochondria in the pheromone- and amiodarone-induced programmed death of yeast

Abstract

Although programmed cell death (PCD) is extensively studied in multicellular organisms, in recent years it has been shown that a unicellular organism, yeast Saccharomyces cerevisiae, also possesses death program(s). In particular, we have found that a high doses of yeast pheromone is a natural stimulus inducing PCD. Here, we show that the death cascades triggered by pheromone and by a drug amiodarone are very similar. We focused on the role of mitochondria during the pheromone/amiodarone-induced PCD. For the first time, a functional chain of the mitochondria-related events required for a particular case of yeast PCD has been revealed: an enhancement of mitochondrial respiration and of its energy coupling, a strong increase of mitochondrial membrane potential, both events triggered by the rise of cytoplasmic [Ca2+], a burst in generation of reactive oxygen species in center o of the respiratory chain complex III, mitochondrial thread-grain transition, and cytochrome c release from mitochondria. A novel mitochondrial protein required for thread-grain transition is identified.

Swapping of the N‐terminus of VDAC1 with VDAC3 restores full activity of the channel and confers anti‐aging features to the cell

“…Actually, similar to mammalian cells, yeast apoptosis is sometimes accompanied by a sharp transient increase of mitochondrial membrane potential that can directly cause accumulation of ROS [33]. A decrease of mitochondrial potential is considered a general marker for in vivo ageing both in mammals and yeast cells [34]. In fact, DASPMI staining performed upon human VDAC-expressing strains in cells aged 3 days showed a dramatic decrease of mitochondrial potential, with an especially negative decrease for VDAC3 carrying cells (Fig.…”

Apoptosis in yeast: triggers, pathways, subroutines

“…Its cytosolic concentration rises following amiodarone (an antiarrhythmic drug) or a-factor-induced apoptosis, eventually leading to mitochondrial fragmentation in a process that depends on the yeast suicide protein Ysp1p. 36 An additional link between yeast death and Ca 2 þ is mediated by the calcineurin/calmodulin system, which is connected to ER stress regulation. 37 In nature, the functional potential of yeast undergoing apoptosis is hijacked for different purposes (see Figure 2).…”

“…40 Treatment of yeast cells with amiodarone also triggers yeast cell death, in this case via the mitochondrial pathway and preceded by a Ca 2 þ boost. 36 The transcriptional response of yeast cells to amiodarone treatment includes two signatures: one that resembles a Ca 2 þ stress response that is accompanied by downregulation of genes involved in all stages of cell-cycle control, and another that is Ca 2 þ -independent and affects nutrient-responsive genes. 41 Diverse other antitumor agents, such as 5-fluorouracil or coumarin, shown to be cytotoxic for yeast, 39 need further investigation regarding the induced mode of cell death in order to establish a possible link to apoptosis.…”

“…Interaction of the pheromone with its receptor (Ste2p or Ste3p) results in activation of the MAP kinase-signaling cascade (which involves the key kinase Ste20p), subsequent increase of intracellular Ca 2 þ , and a rise in mitochondrial activity, followed by cytochrome c release and apoptosis. 12,36 In contrast, death caused by elevated concentrations of pheromone lacks certain hallmarks of apoptosis. 42 Of note, sporulation following meiosis of diploid cells is coupled to apoptosis as well.…”

Selenite-induced cell death in Saccharomyces cerevisiae: protective role of glutaredoxins

“…Thus, mutational disruption of the S. cerevisiae mitochondrial electron transport chain reduces apoptosis caused by copper and manganese (Liang & Zhou, 2007), amiodarone (Pozniakovsky et al, 2005), acetic acid (Ludovico et al, 2002), hyperosmotic stress (Silva et al, 2005) and chronological ageing (Li et al, 2006). We tested how the absence of Ndi1p (mitochondrial inner membrane-associated NADH dehydrogenase) or Cox12p (part of complex IV in the electron transport chain) affected selenite-induced apoptosis.…”