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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM090311-06
Application #
8527801
Study Section
Special Emphasis Panel (ZRG1-BCMB-A (51))
Program Officer
Anderson, Vernon
Project Start
2009-09-30
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
6
Fiscal Year
2013
Total Cost
$640,678
Indirect Cost
$250,219
Name
University of Southern California
Department
Type
Other Domestic Higher Education
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Huffman, Derek M; Farias Quipildor, Gabriela; Mao, Kai et al. (2016) Central insulin-like growth factor-1 (IGF-1) restores whole-body insulin action in a model of age-related insulin resistance and IGF-1 decline. Aging Cell 15:181-6
Sreekumar, Parameswaran G; Ishikawa, Keijiro; Spee, Chris et al. (2016) The Mitochondrial-Derived Peptide Humanin Protects RPE Cells From Oxidative Stress, Senescence, and Mitochondrial Dysfunction. Invest Ophthalmol Vis Sci 57:1238-53
Lee, Changhan; Kim, Kyung Hwa; Cohen, Pinchas (2016) MOTS-c: A novel mitochondrial-derived peptide regulating muscle and fat metabolism. Free Radic Biol Med 100:182-187
Mitchell, Sarah J; Madrigal-Matute, Julio; Scheibye-Knudsen, Morten et al. (2016) Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice. Cell Metab 23:1093-112
Xiao, J; Kim, S-J; Cohen, P et al. (2016) Humanin: Functional Interfaces with IGF-I. Growth Horm IGF Res 29:21-7
Jia, Yue; Ohanyan, Aikoui; Lue, Yan-He et al. (2015) The effects of humanin and its analogues on male germ cell apoptosis induced by chemotherapeutic drugs. Apoptosis 20:551-61
Paharkova, Vladislava; Alvarez, Griselda; Nakamura, Hiromi et al. (2015) Rat Humanin is encoded and translated in mitochondria and is localized to the mitochondrial compartment where it regulates ROS production. Mol Cell Endocrinol 413:96-100
Lue, YanHe; Swerdloff, Ronald; Wan, Junxiang et al. (2015) The Potent Humanin Analogue (HNG) Protects Germ Cells and Leucocytes While Enhancing Chemotherapy-Induced Suppression of Cancer Metastases in Male Mice. Endocrinology 156:4511-21
Lee, Changhan; Zeng, Jennifer; Drew, Brian G et al. (2015) The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab 21:443-54
Lee, Changhan; Wan, Junxiang; Miyazaki, Brian et al. (2014) IGF-I regulates the age-dependent signaling peptide humanin. Aging Cell 13:958-61

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