Fig. 3.

Calcium-centric view of impaired mitochondrial metabolism in NDDs. (1–2) An increase in intracellular calcium by different Ca²⁺ transport systems in the plasma membrane and the endoplasmic reticulum promotes its entry into the mitochondrial matrix via the mtCU. (3) _mCa²⁺ enhances the activity of key TCA enzymes, leading to elevated OxPhos and ATP generation. On the other side, insufficient or excessive _mCa²⁺ content can impair mitochondrial metabolism in NDDs. The ER plays a crucial role in regulating cellular energetics via the regulated release of Ca²⁺ near sites of ER-mitochondrial contact to support ATP production. (4) The changes in mitochondrial dynamics alter respiratory complex assembly and affect the coupling between respiration and ATP synthesis. (5–8) The production of ROS and activation of AMPK signaling by Ca²⁺ and insulin signaling also constitute the diverse array of signaling pathways that elicit transcription regulation of energy metabolism genes