Functional Variation in Mitochondria in Disease Mitochondria are involved in energy metabolism and apoptosis, and contain nearly a thousand proteins, most of which are encoded by the nuclear genome. The mitochondrial chromosome was previously though to encode only 13 proteins that function primarily as components of the mitochondrial electron transport chain. Mitochondrial dysfunction has been associated with many diseases, including neurogegeneration, diabetes and cancer, although its exact role in the development of these diseases remains controversial. In 2001, humanin, a 24-amino-acid peptide proposed to be encoded from the 16S ribosomal RNA of the mtDNA, was described as a potent neurosurvival factor, and we have recently shown it to be a centrally acting in vivo insulin sensitizer. We recently discovered that in addition to humanin, there are six ORFs within the 16S rRNA, and we synthesized the corresponding peptides, which we named SHLPs (small humanin-like peptides). SHLP1-5 potently induce cell survival similarly to humanin, but with different temporal profiles, suggesting that these peptides may act in concert. SHLP6 has opposing actions, inhibiting tumor growth and angiogenesis. We therefore suggest the paradigm-shifting hypothesis that mitochondria play a previously unappreciated role in the regulation of cellular and organismal function through the production of mitochondrial-derived peptides (MDPs). This project has several goals: 1) Identify and verify additional novel MDPs;2) Define the source of MDPs from mitochondrial versus NUMT/nuclear origin;3) Characterize the intracellular trafficking of MDPs;4) Assess the effect of MDPs on cell biology and in vivo physiology;5) Establish MDPs as therapeutic and diagnostic targets in human disease. Humanin and SHLPs are, we believe, the first of many MDPs. These peptides could rapidly emerge as potential diagnostic and therapeutic targets for diseases associated with mitochondrial dysfunction, including neurodegenerative diseases, diabetes and cancer. We therefore propose that mitochondria are not simply energy production and apoptosis-facilitating organelles, but also the source of important bioactive peptides and that the disregulation of these MDPs is important in disease development.

Public Health Relevance

of this research to public health All countries, and particularly the United States, are experiencing a growth in the numbers of elderly people in the population. By 2020 the world population of elderly people is expected to have trebled, with an estimated 700 million people aged 65 years and over of whom 70% will be in developing countries. Of particular significance is the fact that the diseases of the elderly are primarily cancer, Alzheimer's disease and diabetes syndromes, all of which are related to dysfunction of the mitochondria. Opportunities for improving the health of such individuals have been limited. This is due to a variety of factors: negative images of ageing and concepts that health promotion and disease prevention in old age are not worthwhile;and, until relatively recently, neglect by the research community of common problems of old age which require a better understanding of the biological processes involved. Recent studies indicate that growth factors are central to various aging related processes affecting cell survival and senescence and growth factor related therapies have been proposed as possible approaches to the aging problem, including diabetes and Alzheimer's. In our proposed project we will study a family of novel growth and survival factors called MDPs, which appears to be declining with age and may represent therapeutic and diagnostic targets.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BCMB-A (51))
Program Officer
Anderson, Vernon
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Schools of Medicine
Los Angeles
United States
Zip Code
Lee, Changhan; Wan, Junxiang; Miyazaki, Brian et al. (2014) IGF-I regulates the age-dependent signaling peptide humanin. Aging Cell 13:958-61
Widmer, R Jay; Chung, Woo-Young; Herrmann, Joerg et al. (2014) The association between circulating microRNA levels and coronary endothelial function. PLoS One 9:e109650
Cohen, Pinchas (2014) New role for the mitochondrial peptide humanin: protective agent against chemotherapy-induced side effects. J Natl Cancer Inst 106:dju006
Yen, Kelvin; Lee, Changhan; Mehta, Hemal et al. (2013) The emerging role of the mitochondrial-derived peptide humanin in stress resistance. J Mol Endocrinol 50:R11-9
Widmer, R J; Flammer, A J; Herrmann, J et al. (2013) Circulating humanin levels are associated with preserved coronary endothelial function. Am J Physiol Heart Circ Physiol 304:H393-7
Lee, Changhan; Yen, Kelvin; Cohen, Pinchas (2013) Humanin: a harbinger of mitochondrial-derived peptides? Trends Endocrinol Metab 24:222-8
Chin, Yung-Ping; Keni, Jyotsna; Wan, Junxiang et al. (2013) Pharmacokinetics and tissue distribution of humanin and its analogues in male rodents. Endocrinology 154:3739-44
Jia, Y; Lue, Y-H; Swerdloff, R et al. (2013) The cytoprotective peptide humanin is induced and neutralizes Bax after pro-apoptotic stress in the rat testis. Andrology 1:651-9
Zacharias, David G; Kim, Sung Gyun; Massat, Alfonso Eirin et al. (2012) Humanin, a cytoprotective peptide, is expressed in carotid atherosclerotic [corrected] plaques in humans. PLoS One 7:e31065
Oh, Yun K; Bachar, Adi R; Zacharias, David G et al. (2011) Humanin preserves endothelial function and prevents atherosclerotic plaque progression in hypercholesterolemic ApoE deficient mice. Atherosclerosis 219:65-73