Figure 1. Calcium regulation of mitochondrial metabolism.

Calcium (Ca²⁺) released by the sarcoplasmic reticulum is taken up by the mitochondria via the mitochondrial calcium uniporter (MCU). Mitochondria are found in close association with the calcium release channels in the sarcoplasmic reticulum, the ryanodine receptors (RyR), creating a Ca²⁺ microdomain. Mitofusin2 (Mfn2) acts to bring the mitochondria and sarcoplasmic reticulum (SR) into close communication. Ca²⁺ activates (designated by the dashed purple lines) mitochondrial metabolism by increasing the activities of pyruvate dehydrogenase (PDH), isocitrate dehydrogenase (ICDH), and α-ketoglutarate (α-KG) dehydrogenase (α-KDH) resulting in increased metabolism of pyruvate and fatty acyl CoA and increased NADH formation. Ca²⁺ also increases the exchange rate of malate/aspartate (Malate/ASP) shuttle by increasing the activity of the ASP/glutamate (GLUT) exchangers 1 and 2 (AGC1/2), while inhibiting (indicated by the dotted red line) net efflux of citric acid cycle (CAC) intermediates out of the mitochondria via the oxaloacetate (OAA)/malate cotransporter (OMC). The malate/ASP shuttle is responsible for maintaining the cytoplasmic NAD⁺ pool. The 2 spans of the CAC are indicated by blue (reductive span) and green (oxidative span) lines. Pyruvate can feed into the reductive span through PDH or feed into OAA and malate pools in the oxidative span via anaplerotic flux. Ca²⁺ is cleared from the mitochondrial matrix by the actions of the Na⁺/Ca²⁺ exchanger (NCX). The magnitude of the calcium release by the SR is dependent on the actions of SR Ca²⁺-ATPase (SERCA2a), which facilitates Ca²⁺ reuptake into the SR (illustration credit: Ben Smith). FA-CoA indicates fatty acyl-carnitine.