Energy is frequently defined as the ability to perform work, and every work demands some sort of movement. The biggest part of these energetic transformations bioenergetic goes through the mitochondria with also develop an important role as integrators of a variety of intracellular signals. Besides that, this interesting organelle is considered an important local generator of systemic responses. New evidence has pointed the discovery of two peptides named Humanin and mitochondrial Open Reading Frames (ORF) of the twelve S c (MOTS-c), which are derivative from mtDNA and have an important systemic performance. Few works have accomplished studies regarding mitochondrial systemic responses practiced by mitochondrial peptides faced with controlled stress, such as physical stress. Therefore, the goal of this review is to describe the biological effects of these two mitochondrial peptides as well as possible benefic interactions between them and the physical exercise. Thus, we hope that the present review may raise the interest of new clinical studies that better investigate the responses of this new class of peptides faced intervention of the physical exercise, considering the correct manipulation of the components of the training load that modulate both Humanin's response and MOTS-c's response, with therapeutic potential in combating various diseases.