Mitochondria was long thought to be an “end function” organelle that regulated the metabolic flux and apoptosis in the cell. However, with the discovery of humanin (HN/MTRNR2), the first mitochondrial peptide in the early 2000s, the cytoprotective and pro-survival applications of MDPs have taken the forefront of therapeutic and diagnostic research. However, the regulation of humanin-like MDPs in natural model systems that can tolerate lethal environmental and cytotoxic insults remains to be investigated. Red-eared sliders are champion anaerobes that can withstand three continuous months of anoxia followed by rapid bouts of oxygen reperfusion without incurring cellular damage. Freshwater turtles employ extensive physiological and biochemical strategies to combat anoxia, with metabolic rate depression and a global enhancement of antioxidant and cytoprotective pathways being the two most important contributors. The main aim of this study was to uncover and characterize the humanin-homologue in freshwater turtles as well as investigate the differential regulation of humanin in response to short and long-term oxygen deprivation. In this study we have used de novo and homology-based protein modelling to elucidate the putative structure of humanin in red-eared sliders as well as an ELISA and western immunoblotting to confirm the protein abundance in the turtle brain and six peripheral tissues during control, 5 h, and 20 h anoxia (n=4/group). We found that a humanin-homologue (TSE-humanin) is present in red-eared sliders and it may play a crucial cytoprotective role against oxidative damage.