Panel a shows a bar graph comparing isopentenyl pyrophosphate levels between wild-type and cyto-STARD7 HeLa cells treated with dimethyl sulfoxide or pamidronate. The x-axis represents treatment groups, and the y-axis represents isopentenyl pyrophosphate area per one million cells. Panel b shows a bar graph comparing dimethylallyl pyrophosphate levels between wild-type and cyto-STARD7 HeLa cells treated with dimethyl sulfoxide or pamidronate. The x-axis represents treatment groups, and the y-axis represents dimethylallyl pyrophosphate area per one million cells. Panel c shows a schematic model illustrating two cellular states. The left side depicts increased 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity associated with isopentenyl pyrophosphate production, cholesterol synthesis, cholesterol ester formation, mitochondrial coenzyme Q export through STARD7, increased membrane coenzyme Q levels, and ferroptotic resistance. The right side depicts reduced 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity with limited isopentenyl pyrophosphate availability, prioritization of mitochondrial coenzyme Q synthesis, reduced coenzyme Q export, and increased ferroptosis sensitivity.
CoQ distribution upon SCAP inhibition. (a and b) WT and cyto-STARD7 HeLa cells were treated with DMSO or pamidronate (20 µM) for 8 h to inhibit farnesyl pyrophosphate synthase. For each replicate, 1 million cells were used to extract the polar phase using MTBE buffer. The polar phase was then analyzed for IPP (a) and dimethylallyl pyrophosphate (b) (n = 4). The error bars represent the 95% confidence interval. P values are shown above the graphs. (c) Schematic illustrating a potential mechanism by which mitochondria respond to isoprenoid precursor availability. Under conditions of high HMGCR activity and abundant IPP (e.g., cyto-STARD7 overexpression), the model suggests that cells preferentially channel IPP toward cholesterol biosynthesis, leading to cholesterol ester accumulation. This state correlates with enhanced mitochondrial CoQ export, which increases cytosolic CoQ levels and provides resistance to ferroptosis. Conversely, when IPP levels are limited (e.g., SCAP genetic or pharmacological inhibition or HMGCR inhibition), the data support a model where mitochondria prioritize endogenous CoQ synthesis over export, potentially as a survival mechanism that inadvertently sensitizes cells to ferroptosis. Created with BioRender.com.