Peptides encoded in mitochondrial genetic material and their roles in regulating whole-body physiology were the themes of a March 7 visit to NIEHS by Pinchas Cohen, M.D. In a seminar presentation and meetings with researchers, Cohen described his latest findings on the mitochondrial peptide known as humanin, as well as MOTS-c and SHLEPs, which he and his lab discovered.
Cohen, who is dean of the University of Southern California Leonard Davis School of Gerontology, explained how levels of these molecules in the body could be used to asses overall health and the mitochondrial toxicity of chemicals.
Peptides as mitochondrial messengers
Mitochondria are the powerhouses of cells in our bodies. They have their own genetic material that encodes proteins that are fundamental for producing energy through respiration. Among these mitochondrially encoded proteins, Cohen discovered new peptides that act as messengers of mitochondrial function and damage.
“New research has been developed to understand the signals that mitochondria use to communicate within the cell and eventually, to other tissues,” said Janine Santos, Ph.D., staff scientist in the NIEHS Division of Intramural Research. “Dr. Cohen’s research explores a completely new process for this communication.”
Biological effects and levels of mitochondrial peptides
Cohen demonstrated that a variety of cell types recognize and respond to mitochondrial peptides. The most well-studied of these peptides, humanin, protects cells and organisms from various injuries and stressors. Humanin increases energy production, decreases the toxicity of free radicals, and improves overall health in aging animals.
“This is a very intriguing area of mitochondrial research that could have significant pharmaceutical applications,” said Bill Copeland, Ph.D., head of the NIEHS Genome Integrity and Structural Biology Laboratory and a lead researcher.
Cohen recently discovered six short humanin-like peptides, which he named SHLEPs. The biological activities of these six peptides are surprisingly different. SHLEPs 2 and 3 are cellular protectors, like humanin. However, SHLEP 6 is efficient at increasing apoptosis, or killing damaged cells.
“Interestingly, the levels of the different SHLEPs are differently regulated during exposure to environmental toxins,” noted Daniel Shaughnessy, Ph.D., from the NIEHS Division of Extramural Research and Training. Shaughnessy hosted Cohen’s talk.
New potential biomarkers
To help determine the role of mitochondrial peptides in human diseases, Cohen developed assays to detect different SHLEPs in biological samples using NIEHS grant support. “The assays developed are very sensitive, which allow researchers to investigate human diseases and toxicity of environmental poisons that might affect mitochondria,” he explained.
He showed that levels of SHLEPs 2 and 3 decrease in aged mice and after exposure to the chemotherapy drug doxorubicin. Jean Harry, Ph.D., lead researcher in the National Toxicology Program, was one of those interested in the direction of Cohen’s work. “Research on establishing mitochondrial peptides as biomarkers for mitochondrial function in vivo certainly warrants more attention and effort,” she said.
Scientists from all divisions of NIEHS listened as Cohen described using cutting-edge technology, such as next-generation sequencing and population genetics in humans, to work toward characterizing these new mitochondrial peptides.
“Science is complex,” Cohen said. “Each group can bring in only a certain set of expertise and insights, but it is the interaction between researchers in different fields that allows science to move forward.” Judging by the audience, Cohen’s visit brought together NIEHS scientists from many disciplines to learn about this promising field of study.
Xiao J, Kim S-J, Cohen P, Yen K. 2016. Humanin: functional Interfaces with IGF-I. Growth Horm IGF Res 29:21–27.
Lee C, Kim KH, Cohen P. 2016. MOTS-c: a novel mitochondrial-derived peptide regulating muscle and fat metabolism. Free Radic Biol Med 100:182–187.
Kim S-J, Guerrero N, Wassef G, Xiao J, Mehta HH, Cohen P, Yen K. 2016. The mitochondrial-derived peptide humanin activates the ERK1/2, AKT, and STAT3 signaling pathways and has age-dependent signaling differences in the hippocampus. Oncotarget 7(30):46899–46912.
(Douglas Ganini da Silva, Ph.D., is a research fellow in the NIEHS Free Radical Metabolism Group.)