A family of novel mitochondrially-encoded peptides and their role in aging

线粒体参与能量代谢和细胞凋亡，是多种疾病的核心，包括糖尿病、癌症和神经退行性疾病。线粒体含有数百种蛋白质，但线粒体染色体只编码13种蛋白质。2001年，humanin；从mtDNA的16S核糖体RNA区域编码的一种新型24氨基酸肽被描述为一种有效的神经存活因子。几乎在同一时间，我们证明了humanin结合并拮抗促凋亡分子IGFBP-3。在初步未发表的数据中，我们已经表明humanin激活促生存信号级联，并证明它是一种有效的体内胰岛素增敏剂。我们最近发现，除了humanin，在16S rRNA中还有6个额外的orf，我们合成了它们对应的肽，我们将其命名为shlp （small humanin-like peptides）。SHLPs生物活性的初步表征1-5表明，它们是有效的生物活性分子，与人蛋白相似，可诱导细胞存活，但具有不同的时间谱，表明这些肽的作用是一致的。SHLP-6具有相反的作用，抑制细胞生长。这些观察结果表明，线粒体可能在代谢和生存的调节中具有以前未被认识到的作用，这些作用通过线粒体衍生肽（MDPs）的合成发生。线粒体染色体的生物信息学扫描表明，在整个线粒体dna中有超过100个额外的orf。这个尤里卡奖项目旨在描述mdp的表达和特定功能；并试图从功能和基因上将mdp与线粒体相关的衰老疾病联系起来。我们的方法将涉及基因组学和蛋白质组学方法，用于超长寿命的人类和相关的衰老小鼠模型。我们提出，线粒体肽穹窿可以解释线粒体生物学和与衰老相关的功能障碍的重要新方面。这条研究路线与研究人员以前的工作有很大的不同，代表了一个创新的、高风险的项目。所有国家，尤其是美国，都在经历人口中老年人数量的增长。到2020年，世界老年人口预计将增加两倍，65岁及以上的人口估计将达到7亿，其中70%将生活在发展中国家。特别重要的是人口中老年人口的增长，他们的医疗保健和其他需要传统上没有得到解决。改善老年人健康的机会有限。这是由多种因素造成的：对老龄化的负面印象以及认为老年人不值得促进健康和预防疾病的观念；而且，直到最近，研究界对老年常见问题的忽视。特别是老年疾病，包括神经变性、代谢综合征和各种恶性肿瘤，影响到大多数老年人，需要更好地了解所涉及的生物过程。近年来的研究表明，生长因子在影响细胞存活和衰老的各种衰老相关过程中起着核心作用，并提出了与生长因子相关的治疗方法作为解决衰老问题的可能途径。在我们提出的项目中，我们将研究一个名为shlp的新型生长和生存因子家族，它似乎随着年龄的增长而下降，可能代表治疗和诊断目标。

Description (provided by applicant): 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 In preliminary unpublished data, we have shown that humanin activates a pro-survival signaling-cascade and demonstrated that it is a potent in vivo insulin sensitizer.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.