Professor Juhan Sedman, University of Tartu
Professor Xin Jie Chen, SUNY Upstate Medical University, Syracuse, NY, USA
Mitochondria are often compared to powerhouses of the cell since they are responsible for energy production through oxidative phosphorylation. They also coordinate cellular metabolism through synthesis and degradation of metabolic intermediates. To ensure that the amount of energy equivalents and metabolic intermediates produced by the mitochondria matches the cellular requirements, the mitochondrial function(s) and activities are modulated by the conserved signaling pathways, such as the cAMP-PKA and TOR signaling. These pathways monitore both intra- and extracellular nutritional environment and coordinate diverce processes, among them mitochondrial activities, cellular morphology and aging.
The model yeast Saccharomyces cerevisiae has been widely used to study the effects of mitochondrial dysfunction on various cellular processes. It has been shown previously that the functional mitochondria are essential for switch to filamentous growth in this yeast. However, it is unclear by which mechanism mitochondrial dysfunction influences this process. Since the filamentous growth has been connected to virulence determinants in opportunistic commensal fungi, it has remained under extensive study in S. cerevisiae. The main objective of this study was to determine how the dysfunctional state of mitochondria interferes with filamentous growth and affects responses to starvation conditions. It was shown that in the respiratory deficient mutants the transcription of well described filamentous growth target FLO11 is downregulated and induction of FLO11 expression restores the response. By monitoring the activities of several signaling pathways it was shown that mitochondrial dysfunction specifically downregulates the cAMP-PKA signaling. Analysis of phenotypic traits indicated that the effect of respiratory dysfunction on cAMP-PKA pathway activity depends on genetic background of the strain and is therefore probably interpreted according to specific cellular metabolic context. In addition, validation of computational method m:Explorer revealed several new candidate regulators of chronological aging in yeast. The most pronounced effects were observed with BAS1, MGA2, CST6 deletion strains where significant life span extension was demonstrated. It was further shown that respiratory deficiency of different mutants does not lead to uniformly decreased viability dynamics and the exact type of mitochondrial dysfunction, or accompanying cellular rearrangements of specific mutants appear to play a role in longevity determination. It can be concluded that mitochondrial dysfunction affects morphological differentiation program through rearrangement of cellular signaling network. Importantly, the effect of mitochondrial dysfunction on morphological differentiation and also on chronological aging is probably interpreted according to specific cellular context and depends on yeast strain and/or metabolic context of the cell.