A family of novel mitochondrially-encoded peptides and their role in aging Abstract Mitochondria are involved in energy metabolism and apoptosis, and are central to multiple diseases, including diabetes, cancer, and neurodegeneration. Mitochondria contain hundreds of proteins, but the mitochondrial-chromosome only encodes 13 proteins. In 2001, humanin;a novel 24-amino-acid peptide encoded from the 16S ribosomal RNA region of the mtDNA, was described to be a potent neurosurvival factor. Almost at the same time we demonstrated that humanin binds and antagonizes the proapoptotic-molecule IGFBP-3. In preliminary unpublished data, we have shown that humanin activates a pro-survival signaling-cascade and demonstrated that it is a potent in vivo insulin sensitizer. We recently discovered that in addition to humanin, there are six additional ORFs within the 16S rRNA and we synthesized their corresponding peptides, which we named SHLPs (small humanin-like peptides). Initial characterization of the biological activity of the SHLPs 1-5 indicates that they are potent bioactive molecules acting to induce cell survival similarly to humanin, but with different temporal profiles, suggesting that these peptides act in concert. SHLP-6, has opposing actions, inhibiting cell growth. These observations suggest that the mitochondria may possess previously unappreciated roles in the regulation of metabolism and survival that occur via the synthesis of mitochondrial-derived peptides (MDPs). A bioinformatics scan of the mitochondrial chromosome indicates that there are over 100 additional ORFs throughout the mtDNA. This EUREKA Award project proposes to characterize the expression and specific functions of MDPs;and to try to functionally and genetically link MDPs to mitochondrially-related diseases of aging. Our approach will involve genomic and proteomic approaches in humans with exceptional longevity and in relevant mouse models of aging. We propose that the mitochondrial peptidome could explain important new aspects of mitochondrial biology and dysfunction with relevance to a aging. This line of research is a dramatic shift from the investigators previous work, and represents a innovative, high-risk project. 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 growth of the oldest old in the population whose medical care and other needs have not been traditionally addressed. Opportunities for improving the health of elderly people 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. In particular diseases of aging, including neurodegeneration, metabolic syndrome, and various malignancies, affect the majority of the elderly and 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. In our proposed project we will study a family of novel growth and survival factors called SHLPs, which appears to be declining with age and may represent therapeutic and diagnostic targets.

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 growth of the oldest old in the population whose medical care and other needs have not been traditionally addressed. Opportunities for improving the health of elderly people 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. In particular diseases of aging, including neurodegeneration, metabolic syndrome, and various malignancies, affect the majority of the elderly and 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. In our proposed project we will study a family of novel growth and survival factors called SHLPs, which appears to be declining with age and may represent therapeutic and diagnostic targets.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG034430-03
Application #
8080199
Study Section
Special Emphasis Panel (ZAG1-ZIJ-7 (M1))
Program Officer
Finkelstein, David B
Project Start
2009-07-15
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
3
Fiscal Year
2011
Total Cost
$295,944
Indirect Cost
Name
University of California Los Angeles
Department
Pediatrics
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Xiao, Jialin; Howard, Lauren; Wan, Junxiang et al. (2017) Low circulating levels of the mitochondrial-peptide hormone SHLP2: novel biomarker for prostate cancer risk. Oncotarget 8:94900-94909
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Ben-Avraham, Danny; Govindaraju, Diddahally R; Budagov, Temuri et al. (2017) The GH receptor exon 3 deletion is a marker of male-specific exceptional longevity associated with increased GH sensitivity and taller stature. Sci Adv 3:e1602025
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; 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
Widmer, R Jay; Widmer, Jocelyn M; Lerman, Amir (2015) International collaboration: promises and challenges. Rambam Maimonides Med J 6:e0012
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
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
Lee, Changhan; Wan, Junxiang; Miyazaki, Brian et al. (2014) IGF-I regulates the age-dependent signaling peptide humanin. Aging Cell 13:958-61
Cohen, Pinchas (2014) New role for the mitochondrial peptide humanin: protective agent against chemotherapy-induced side effects. J Natl Cancer Inst 106:dju006

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