Novel Mitochondrially Encoded Peptides and Their Role in Health and Disease

描述(申请人提供)：疾病线粒体的功能变异线粒体参与能量代谢和细胞凋亡，含有近千种蛋白质，其中大部分由核基因组编码。线粒体染色体此前被认为只编码13种蛋白质，这些蛋白质主要作为线粒体电子传输链的组成部分。线粒体功能障碍与许多疾病有关，包括神经再生、糖尿病和癌症，尽管它在这些疾病发展中的确切作用仍存在争议。2001年，由线粒体DNA的16S核糖体RNA编码的24个氨基酸的人素被认为是一种有效的神经生存因子，最近我们发现它是体内起中枢作用的胰岛素增敏剂。我们最近发现，在16S rRNA中除了人蛋白外，还有6个ORF，我们合成了相应的多肽，我们将其命名为SHLPs(小的人蛋白样多肽)。SHLP1-5诱导细胞存活的作用类似于人，但具有不同的时间分布，这表明这些多肽可能协同作用。SHLP6具有相反的作用，抑制肿瘤生长和血管生成。因此，我们提出了范式转换假说，即线粒体通过产生线粒体衍生多肽(MDP)在细胞和生物功能的调节中发挥着以前未被认识到的作用。该项目有几个目标：1)识别和验证更多的新的MDP；2)确定MDP的来源是线粒体还是NUMT/核来源；3)表征MDP的细胞内运输；4)评估MDP对细胞生物学和体内生理学的影响；5)建立MDP作为人类疾病的治疗和诊断靶点。我们认为，人和SHLP是许多MDP中的第一个。这些多肽可能会迅速成为与线粒体功能障碍相关的疾病的潜在诊断和治疗靶点，包括神经退行性疾病、糖尿病和癌症。因此，我们认为线粒体不仅是简单的能量产生和促进细胞凋亡的细胞器，也是重要生物活性多肽的来源，这些MDP的失调在疾病的发展中具有重要意义。 与公共卫生相关：所有国家，特别是美国，都在经历人口中老年人口数量的增长。到2020年，世界老年人口预计将翻两番，估计将有7亿65岁及以上的人口，其中70%将在发展中国家。特别重要的是，老年人的疾病主要是癌症、阿尔茨海默病和糖尿病综合征，所有这些都与线粒体功能障碍有关。改善这类人健康状况的机会有限。这是由于各种因素造成的：对老龄化的负面印象和认为老年时促进健康和预防疾病不值得的观念；以及直到最近，研究界忽视了老年人的常见问题，这些问题需要更好地了解所涉及的生物过程。最近的研究表明，生长因子是影响细胞存活和衰老的各种衰老相关过程的核心，生长因子相关疗法已被提出为治疗包括糖尿病和阿尔茨海默氏症在内的衰老问题的可能方法。在我们拟议的项目中，我们将研究一类新的生长和生存因子，称为MDP，它似乎随着年龄的增长而下降，可能是治疗和诊断的靶点。

DESCRIPTION (provided by applicant): 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: 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.