Abstract
BackgroundAppropriate control of mitochondrial function, morphology and biogenesis are crucial determinants of the general health of eukaryotic cells. It is therefore imperative that we understand the mechanisms that co-ordinate mitochondrial function with environmental signaling systems. The regulation of yeast mitochondrial function in response to nutritional change can be modulated by PKA activity. Unregulated PKA activity can lead to the production of mitochondria that are prone to the production of ROS, and an apoptotic form of cell death.ResultsWe present evidence that mitochondria are sensitive to the level of cAMP/PKA signaling and can respond by modulating levels of respiratory activity or committing to self execution. The inappropriate activation of one of the yeast PKA catalytic subunits, Tpk3p, is sufficient to commit cells to an apoptotic death through transcriptional changes that promote the production of dysfunctional, ROS producing mitochondria. Our data implies that cAMP/PKA regulation of mitochondrial function that promotes apoptosis engages the function of multiple transcription factors, including HAP4, SOK2 and SCO1.ConclusionsWe propose that in yeast, as is the case in mammalian cells, mitochondrial function and biogenesis are controlled in response to environmental change by the concerted regulation of multiple transcription factors. The visualization of cAMP/TPK3 induced cell death within yeast colonies supports a model that PKA regulation plays a physiological role in coordinating respiratory function and cell death with nutritional status in budding yeast.
Highlights
Appropriate control of mitochondrial function, morphology and biogenesis are crucial determinants of the general health of eukaryotic cells
Results cAMP/protein kinase A (PKA) regulation of respiratory function Our previous studies have shown that aggregation of the actin cytoskeleton results in hyperactivation of the Ras/ cAMP/PKA signaling pathway, leading to the loss of respiratory function, reactive oxygen species (ROS) production and an apoptotic cell death [27]
It should be noted that the overexpression of HAP4 in wild type cells resulted in a significant reduction in oxygen consumption (Figure 7B) and an increase in the number or ROS positive cells (Figure 7C). These results suggest that increased expression of HAP4 can lead to an increase in mitochondrial biogenesis, it does not by itself lead to the production of healthy and fully functional organelles
Summary
Appropriate control of mitochondrial function, morphology and biogenesis are crucial determinants of the general health of eukaryotic cells. Mitochondria participate in a number of essential cellular functions, for example they are key players in ATP production, via the process of oxidative phosphorylation, which can produce up to 15 times more ATP from glucose than glycolysis alone. They are central to metabolic regulation and facilitate diverse cell signaling events [1,2]. Mitochondria are essential for the maintenance, adaptability and survival of eukaryotic cells These remarkable organelles have been conclusively shown to play a role in the regulation of programmed cell death processes (reviewed in [3]), and act as an important determinants of cellular senescence and ageing [4,5]. Mitochondrial dysfunction can lead to the production of reactive oxygen species (ROS), which are implicated in both ageing and apoptosis [12,13], presumably as a result of their ability to damage macromolecules
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