Investigating the role of mitochondria in regulating cell health and ageing

Reactive oxygen species (ROS) are highly reactive oxygen-containing compounds which are thought to have detrimental effects on cell health and ageing. Mitochondrial dysfunction is generally considered to elevate ROS production due to respiratory enzymes in the electron transport chain (ETC) engaging in side reactions with oxygen. However, countless attempts to alleviate mitochondrial ROS accumulation in model organisms have failed to yield improvements in cellular health or ageing. In addition, respiratory-incompetent Saccharomyces cerevisiae cells lacking the ETC CIV subunit Cox4p accumulate high levels of ROS not via the ETC, but via an ER-bound NADPH oxidase named Yno1p. The loss of Cox4p causes Ras2p to associate with the mitochondrial outer membrane, repressing the degradation of Yno1p by the endoplasmic reticulum-associated degradation pathway (ERAD). This process is in turn dependent on the bromodomain-containing transcription factor, Bdf1p, which, in Δcox4 cells, appears to dissociate from acetyl-lysine residues in histone tails and localise to the mitochondria alongside Ras2p. Here I propose that by impairing mitochondrial function, the loss of Cox4p downregulates cytosolic acetyl-CoA biosynthesis, resulting in histone hypoacetylation, and that by dissociating from hypoacetylated histones, Bdf1p serves to tether the histone acetylation state to ROS accumulation in Δcox4 cells. I demonstrate that the loss of Cox4p elevates ROS levels approximately 37-fold relative to WT cells and is associated with the downregulation of many genes involved in acetyl-CoA biosynthesis. Further, I show that the loss of Cox4p is associated with the downregulation of genes enriched for acetylated histone lysine residues. Lastly, I demonstrate that increasing the levels of acetyl-CoA, either by overexpressing the cytosolic acetyl-CoA synthetase ACS2 or by supplementing cultures with potassium acetate, is sufficient to decrease ROS accumulation in Δcox4 cells and, in the case of the latter intervention, virtually eliminate it. These results indicate that defective acetyl-CoA metabolism is crucial for the accumulation of ROS in Δcox4 cells, and ought to spur further research into the links between metabolism and ROS accumulation in other organisms and under different conditions of respiratory deficiency.