傅磊課題組階段性地完成了“通過化學手段干預線粒體活性”的研究，在PNAS雜誌上刊出文章 “Moderation of mitochondrial respiration mitigates metabolic syndrome of aging” 。
Mito-Fu 或能延長人類健康壽命的藥物
Mito-Fu, Probable Drugs for Human Health Span
人類健康壽命(Health Span)是指他健康的時間長度，而不僅僅是活著的時間。根據美國國家科學院院刊(PNAS)2020年4月17日的一篇文章[1]，上海交通大學和斯坦福大學的科學家們設計了一類新化合物，2-(2-(4-甲基噻唑-5-基)乙氧基)-2-氧乙基三唑的三苯基膦衍生物(簡稱TPP-噻唑，是Mito-Fu家族的成員)。在小鼠體內，這類化合物能精準地靶向線粒體，緩解衰老相關的疾病，阻止年齡相關性肥胖和血糖併發症的發生，並延長小鼠健康壽命。
A person’s health span is the length of time that the person is healthy – not just alive. According to a paper in the April 2020 issue of Proceedings of the National Academy of Sciences of the United States of America (PNAS)[1], scientists from Shanghai Jiao Tong University (SJTU) and Stanford University designed a novel drug, a triphenyl-phosphonium derivative of the 2-(2-(4-methylthizol-5-yl) ethoxy)-2-oxoethyl triazole (TPP-thiazole), a member of Mito-Fu family. This compound specifically targets mitochondria and consequentially alleviates aging diseases, impedes the onset of age-associated obesity, blood glucose complications, and improves health span in mice.
該論文的通訊作者、上海交通大學藥學院傅磊教授說，“我們發現了一種獨特的作用機制，它可以提高模型動物的線粒體數量和質量。從小鼠身上觀察到的這些令人信服的結果表明，基於這種獨特的機制，這類化合物值得進一步研究，並會有許多潛在的臨床應用。”
“We have discovered a proprietary mechanism to improve mitochondrial quality and quantity in the animal model.” says Professor Fu at SJTU School of Pharmacy, a corresponding author of this PNAS paper, “these compelling results in mice show that the impact of this compound deserves a closer look as there are many potential clinical applications based on this proprietary mechanism.”
斯坦福大學的Collman教授強調：“這項研究報道了一種新型、無害的藥物，它能抑制小鼠的呼吸，大大降低衰老的不利影響，並促進新的線粒體產生。線粒體是所有依賴空氣生存動物的能量工廠。Mito-Fu是一類水溶性化合物，還可以用來治療II型糖尿病和炎症相關的疾病。”
“This study reports a new, seemingly innocuous drug that inhibits respiration in mice, strongly diminishing the adverse effects of aging and creating new mitochondria, the power cells of all air-breathing animals. This water-soluble compound treats type II diabetes and reduces inflammation.” Professor Collman at Stanford emphasizes.
線粒體存在於真核細胞，它將營養物質轉化為能量，但線粒體的功能會隨年齡增加而衰退。該研究論文的第一作者，傅磊課題組的博士研究生M. Tavallaie解釋道：“線粒體就像體內的發電機，提供細胞運行所需的能量，但同時也會產生有害的‘副產物’。這些副產物會加速衰老，引起年齡相關性疾病。因此，我們通過干預細胞器，誘導有規律的停頓，使它們恢復活力。”
Mitochondria are the part of eukaryotic cells that convert nutrients to create energy. Mitochondria decay with age. “Mitochondria are like a furnace in the body; they produce energy but at the same time make harmful byproducts which accelerate aging and expedite the age-linked diseases. Therefore, we believe that this intervention by inducing a regulated pause to these organelles allows them to rejuvenate,” according to the study's lead author, M. Tavallaie, a Ph.D. candidate in Dr. Fu’s lab at SJTU School of Pharmacy.
這項研究源自於一類仿生化合物的合成，該化合物模擬線粒體中的細胞色素c氧化酶(CcO)。基於這種模擬酶，斯坦福大學Collman教授的研究團隊發現了一系列新的化合物[2-6]。
This research stemmed from the synthesis of a biomimetic compound that imitates the respiratory enzyme, cytochrome c oxidase (CcO) in the mitochondria. Based on this enzymatic mimic a series of novel compounds were discovered by the Collman group at Stanford [2-6].
在這篇PNAS文章中，傅磊教授的研究小組將60只雄性小鼠隨機分為給藥組和對照組，在18個月的給藥過程中，研究人員檢測了線粒體的多項功能，如呼吸能力、線粒體生物能量和生物合成，以及一些與衰老相關的指標，包括小鼠的活性氧化物(ROS)生成、葡萄糖異常和肥胖。研究結果表明，慢性中度抑制CcO可減少ATP合成，促進線粒體生成和線粒體自噬，從而減少ROS生成和線粒體衰退，調控重要的細胞能量代謝調節因子;因此，該化合物可以有效地調節能量平衡，抑制肥胖和與衰老相關的葡萄糖異常。
In this PNAS paper, the SJTU research team randomly divided 60 male mice into compound-treated and control groups and characterized a variety of mitochondrial functions, such as respiratory activity, mitochondrial bioenergetics, and biogenesis, and few age-associated comorbidities including reactive oxygen species (ROS) production, glucose abnormalities and obesity in mice over a period of 18-month treatment. The team was able to demonstrate that chronic moderate inhibition of CcO reduces ATP synthesis, promotes mitochondrial biogenesis and mitophagy, subsequently decreasing ROS production and mitochondrial decay, and rectifying vital cellular energy metabolism regulators; thus, effectively refining energy homeostasis and curbing obesity and glucose irregularities linked to aging.
“我們已經證明，Mito-Fu系列的一個成員可以促進新陳代謝，緩解衰老併發症。新的衍生化合物正在進一步的研究中。未來的研究會在更大的動物身上測試這些藥物，並最終用到人身上。”傅磊教授說到，“目前我們已經合成了大量具有活性的低毒性小分子化合物，還發現了提高這類新藥活性的簡單策略。深入瞭解其作用機制使我們能夠開發出活性更好的化合物，針對特定疾病予以臨床干預。”
“We have demonstrated that a member of Mito-Fu family boosts metabolism and mitigates aging complications. New derivatives are being examined for efficacy. Future research will test these drugs on larger animals with an ultimate application in humans.” Dr. Fu added, “at this point, we have uncovered a myriad of active compounds. These are small molecules with low levels of toxicity. We have also discovered a simple strategy to increase the activity of this new class of drugs. Understanding the underlying mechanism may allow us to develop even more active chemicals directed specifically in particular disease states and to translate the intervention in humans.”
References：
[1] M. Tavallaie, R. Voshtani, X. Deng, Y. Qiao, F. Jiang, J. P. Collman, L. Fu, “Moderation of Mitochondrial Respiration Mitigates Metabolic Syndrome of Aging” Proc. Natl. Acad. Sci., April 2020.
https://doi.org/10.1073/pnas.1917948117(點擊閱讀原文)
[2] J. P. Collman, L. Fu, P. C. Herrmann and X. Zhang, “A Functional Model Related to Cytochrome c Oxidase and Its Electrocatalytic Four-Electron Reduction of Dioxygen” Science, 275(1997)949.
[3] J. P. Collman, L. Fu, P. C. Herrmann, Z. Wang, M. Rapta, M. Broring, R. Schwenninger and B. Boitrel, “A Functional Model of Cytochrome c Oxidase — Thermodynamic Implication” Angew. Chem. Eng. Edition, 37(1998)3397.
[4] J. P. Collman and L. Fu, “Synthetic Models for Hemoglobin and Myoglobin” Acc. Chem. Res., 32(1999)455.
[5] J. P. Collman, R. Boulatov, C. Soundland and L. Fu, “Functional Analogs of Cytochrome c Oxidase, Hemoglobin and Myoglobin” Chem. Rev., 104(2004)561-588.
[6] C. Barile, P. C. Herrmann, D. A. Tyvoll, J. P. Collman, R. A. Decreau and B. S. Bull, “Inhibiting platelet-stimulated blood coagulation by inhibition of mitochondrial respiration” Proc. Natl. Acad. Sci., 109(2012)2539.
