Orthograde sarcoplasmic reticulm (SR)-mitochondrial signaling (solid lines) involves calcium (Ca2+) release during excitation-contraction (EC) coupling being taken up into adjacent mitochondria to stimulate oxidative phosphorylation (OXPHOS) and adenosine triphosphate (ATP) production. Retrograde mitochondrial-SR signaling (broken lines) involves the influence of mitochondrial reactive oxygen species (ROS) production and scavenging/detoxification on the local redox environment and local Ca2+ spark activity of the Ca2+ release unit (CRU). SR, sarcoplasmic reticulum; RyR1, type 1 ryanodine receptor; DHPR, dihydropyridine receptor; TT, transverse tubule; SERCA, sarco(endo)plasmic reticulum Ca2+-ATPase.