This review focuses on the different mechanisms involved in the adjustment of mitochondrial ATP production to cellular energy demand. The oxidative phosphorylations steady state at constant mitochondrial enzyme content can vary in response to energy demand. However, such an adaptation is tightly linked to a modification in both oxidative phosphorylations yield and phosphate potential and is obviously very limited in eukaryotic cells. We herein describe the three main mechanisms involved in mitochondrial response to energy demand. In heart cells, a short-term adjustment can be reached mainly through metabolic signaling via phosphotransfer networks by the compartmentalized energy transfer and signal transmission. In such a complex regulatory mechanism, calcium signaling participates in an activation of matricial dehydrogenases as well as of the mitochondrial ATP synthase. These processes allow a large increase in ATP production rate without any important modification in thermodynamic forces. For a long term adaptation two main mechanisms are involved: the modulation of the mitochondrial enzyme content as a function of energy demand and/or kinetic regulation by covalent modifications (phosphorylations) of some respiratory chain complexes subunits. Regardless of the mechanism involved (kinetic regulation by covalent modification or adjustment of the mitochondrial enzymatic content), the cAMP signaling pathway plays a major role in the molecular signaling leading to the mitochondrial response. We will discuss the energetic advantages of these mechanisms.