Mitochondrial origins of fractional control in regulated cell death

https://www.nature.com/articles/s41467-019-09275-x.pdf

Luís C. Santos, Robert Vogel, Jerry E. Chipuk, Marc R. Birtwistle, Gustavo Stolovitzky & Pablo Meyer

• The authors investigate cell-to-cell variability in cell death in response to TNF-related apoptosis inducing ligand (TRAIL), an apoptosis-inducing drug.
• The authors find that with successively increasing doses of TRAIL, the probability distribution of mitochondrial density (which the authors define as MitoTracker Deep Red fluoresence intensity divided by forward scatter) becomes increasingly enriched for cells with high mitochondrial density -- suggesting that high cytoplasmic mitochondrial density is required for TRAIL resistance (in contrast to this)
• The authors point out that the steepness of a dose-response curve is a measure of cell-to-cell variability in cellular sensitivity to a stimulus, and derive a formalism to convert a Hill function into a probability distribution over cellular stimulus thresholds for a binary response variable (such as cell death). They derive an approximate expansion of the sensitivity threshold in terms of the half maximal inhibitory concentration (IC50), and the log ratio of mitochondrial density to mean mitochondrial density. This results in an expression for the conditional probability of a cell being alive given a biological quantity of interest, e.g. mitochondrial density (see Eq 4)
• The authors attribute this correlation to variable effective concentrations of pro-apoptotic proteins on the mitochondrial outer membrane
• The authors suggest that anti-apoptotic Bcl-2 family proteins may increase the variance in cell death response, potentially enhancing resistance to treatment