Humanin-induced autophagy plays important roles in skeletal muscle function and lifespan extension

• Published in: Biochimica et biophysica acta. General subjects Vol. 1866; no. 1; p. 130017
• Main Authors: Kim, Su-Jeong, Devgan, Anjali, Miller, Brendan, Lee, Sam Mool, Kumagai, Hiroshi, Wilson, Kenneth A., Wassef, Gabriella, Wong, Richard, Mehta, Hemal H., Cohen, Pinchas, Yen, Kelvin
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2022
• Subjects: Aging; Animals; Autophagy; Autophagy - physiology; Caenorhabditis elegans - metabolism; Cell Line; Cell Survival; cell viability; HEK293 Cells; Homeostasis; Humanin; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Intracellular Signaling Peptides and Proteins - physiology; Lifespan; Longevity; Male; Mice; Mice, Inbred C57BL; mitochondria; Mitochondria - metabolism; Mitochondrial-derived peptides; Muscle, Skeletal - metabolism; Muscle, Skeletal - physiology; peptides; Peptides - metabolism; skeletal muscle; therapeutics; Mitochondrial-derived peptides; Autophagy; Lifespan; Humanin
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2021.130017

Autophagy, a highly conserved homeostatic mechanism, is essential for cell survival. The decline of autophagy function has been implicated in various diseases as well as aging. Although mitochondria play a key role in the autophagy process, whether mitochondrial-derived peptides are involved in this process has not been explored. We developed a high through put screening method to identify potential autophagy inducers among mitochondrial-derived peptides. We used three different cell lines, mice, c.elegans, and a human cohort to validate the observation. Humanin, a mitochondrial-derived peptide, increases autophagy and maintains autophagy flux in several cell types. Humanin administration increases the expression of autophagy-related genes and lowers accumulation of harmful misfolded proteins in mice skeletal muscle, suggesting that humanin-induced autophagy potentially contributes to the improved skeletal function. Moreover, autophagy is a critical role in humanin-induced lifespan extension in C. elegans. Humanin is an autophagy inducer. This paper presents a significant, novel discovery regarding the role of the mitochondrial derived peptide humanin in autophagy regulation and as a possible therapeutic target for autophagy in various age-related diseases. •This is the first report of humanin being associated with macroautophagy.•Humanin administration induces autophagy in three different cell lines, while humanin siRNA treatment reduces the basal autophagy levels.•Humanin administration in old mice increases autophagy-related gene and improves exercise capacity.•Humanin is co-expressed with autophagy-related genes in human brains.