Fig. 9: Scheme of possible relationships between FAD mutations, mitochondrial-ER interaction, mitochondrial and ER Ca²⁺ signaling, bioenergetic status of mitochondria, ER-stress/UPR and protein synthesis.

FAD mutations-provoked increase in short distance mitochondrial-ER contact sites may lead to (1) deficient mitochondrial Ca²⁺ signaling, (2) decrease of OxPhos function and production of ATP and (3) to increase of ROS. From the ER side it may lead to (4) overload of the ER with Ca²⁺ and deregulation of cellular Ca²⁺ homeostasis, (5) induction of ER-stress/UPR response as well as (6) to inhibition of protein synthesis (red arrows). Secondary events may include negative feedbacks of the ATP deficit and the increased ROS on (7) the cellular Ca²⁺ homeostasis and (8) protein synthesis (orange arrows).