Mitochondria in aging cell differentiation

key organelles of eukaryotic cells that are responsible for essential metabolic processes, generation of energy, cellular redox state and many other processes, are deeply involved in cellular homeostasis and influence overall cell/organism physiology. Defects in mitochondria can lead to a number of different disorders in mammals [1]. Changes in the functional state of mitochondria can induce cellular responses via activation of " mitochondrial retrograde signaling " pathway(s). Such responses often result in changes in gene expression and overall cell physiology leading to the prevention of cell death, as described in mammals and yeast [2]. In mammals, physiological changes induced by retrograde signaling are often linked to cancer-related disorders, including the activation of different oncogenic factors and enzymes involved in aerobic glycolysis [1]. The major pathway involved in retrograde signaling in yeast (the RTG pathway) is mediated by three activators Rtg1p, Rtg2p and Rtg3p. Rtg2p transfers the signal from mitochondria to the Rtg1p/Rtg3p heterodimeric transcriptional activator that translocates from cytosol to nucleus and activates expression of numerous genes involved in yeast metabolic reprogramming. The RTG pathway is negatively regulated by Mks1p and Bmh1p/2p. TORC1 negative regulation has also been observed [3]. The activation of anaplerotic reactions and peroxisomal functions, including the glyoxylate cycle, has long been considered to be a major RTG pathway response in yeast and the CIT2 gene, encoding the peroxisomal isoform of citrate synthase, as a typical target of the RTG pathway. Recently, we have provided evidence that the RTG response in yeast is more complex than previously assumed, involves a number of yet to be identified regulatory elements and affects different cellular processes and the subsequent fate of differentiated yeast cells [4]. In differentiated yeast colonies we have identified 3 different branches of RTG signaling, regulated by differently altered mitochondria and leading to expression of different gene targets and thus to divergent metabolic reprogramming. These findings build upon our previous identification on two major cell types that develop within ageing, differentiated colonies, regulated by ammonia signaling-vital U cells in upper colonial regions that gain unique metabolic Editorial properties important for the longevity of these cells and starving, respiration-competent L cells in lower regions that provide nutrients to U cells [5, 6]. Dampened, ROS-free mitochondria activate the " Ato-branch " of RTG signaling in modestly respiring U cells, leading to the activation of expression of ATO1 and ATO2 genes, involved in ammonia production and metabolic reprogramming of these …