粒線體活性氧誘導適應性效益（又稱粒線體興奮效應）（Mitohormesis）是
指藉由提升適量的粒線體活性氧（Reactive oxygen species, ROS）而誘導適應性的細胞保護反應產生，藉由這些反應最後達到整體性生物抗壓效益提升的一
種現象。在生物老化的過程中，粒線體興奮效應帶來許多好處，其一則是延長
壽命。近期有文獻指出，對於環境變化所給予生物損傷的壓力，像是粒線體活
性氧曝露等，可以透過調控染色體結構鬆緊及其相關結合蛋白進而調控基因表
達之表觀遺傳（Epigenetics）相關機制進行調節，並產生適應性反應。其中參
與調控染色體結構鬆緊的結合蛋白，異染色質蛋白1（Heterochromatin Protein 1,HP1），在人類細胞中已經知道其含量與老化呈現反比之關係，另外在果蠅研
究中也發現透過促進異染色質結構形成可以達到延長壽命的效果。雖然在粒線
體興奮效應或是異染色質都達到延年益壽的效用，但是目前仍未有研究針對異
染色質在粒線體興奮效應調控上所扮演的角色進行相關調查。因此，我們使用
果蠅作為動物模式系統，針對在肌肉粒線體擾動所造成之粒線體興奮效應過程
中是否受到異染色質調節之基因的調控進行探討。我們觀察到在肌肉之粒線體
興奮效應過程中，異染色質及活性氧含量會呈現動態的改變。生物受到肌肉粒
線體擾動後，在幼年發育時期（此時期即為肌肉之粒線體興奮效應早期）呈現
異染色質含量減少及活性氧增加之現象，但有趣的是在生物成年時期，異染色
質的含量是增加的，活性氧含量為減少之狀態。此外，我們根據HP1 RNAi 微
陣列線上資料及先前文獻篩選粒線體興奮效應相關基因，找出七個可能在粒線
體興奮效應中受異染色質蛋白1 調控的候選基因。有趣的是，我們進一步發現
異染色質可能透過調控MyD88 （一種 NF-κB 的活化劑）而參與在粒線體興奮
效應調控過程。在我們的研究中，值得注意的是異染色質調控基因表達之效應
不只出現在受到粒線體干擾之肌肉組織上，其效應也被發現在非肌肉組織中，
例如我們觀察到在肌肉粒線體擾動過程中，LK6（哺乳動物的Mnk1 和Mnk2
同源基因）為異染色質調控基因之一，其表達量不但在肌肉組織中上升，在全
身其他非肌肉組織中也是上升的。綜合上述，這些結果表明在肌肉粒線體興奮
效應中，異染色質整體性調控生物細胞核基因表達可能在促進壽命延長效益中
扮演重要調控之角色。這項研究對於生物因應環境壓力時所進行的表觀遺傳調
節機制可以有更進一步的了解。並且這樣的研究可能有助於老化相關慢性疾病
的治療與預防。

Mitochondrial hormesis (mitohormesis) is an adaptive cytoprotective response, which is induced by appropriate levels of mitochondrial reactive oxygen species (ROS). Mitohormesis brings beneficial effects of organisms, such as extending lifespan. Recent evidence has shown that epigenetic regulatory mechanisms, via chromatin binding proteins, mediate adaptive responses to environmental stressors such as ROS. Heterochromatin protein 1 (HP1), an evolutionarily conserved chromatin binding protein essential for heterochromatin formation, promotes longevity in human cells and Drosophila. Here, we use Drosophila as a model to determine whether and how heterochromatin mediates muscle mitohormesis via nuclear gene expression. We show that muscle mitohormesis induces dynamic changes in the heterochromatin and ROS levels. Animals with muscle mitohormesis show less heterochromatin and more ROS in the early phase during larval development, but more heterochromatin and less ROS in the adult stage, as compared to non-mitohormetic animals of the same age. Furthermore, by studying the common targets of both HP1 RNAi microarray data and mitohormesis-related genes from a previous genetic screen, we find seven mitohormesis-related genes, which are also regulated by HP1. Interestingly, myeloid differentiation primary response 88 (Myd88) in the NF-κB pathway may be regulated by heterochromatin in mitohormesis. Strikingly, the effect of muscle mitohormesis on heterochromatin levels is propagated to other non-muscle tissues, whereas Lk6 (a homolog to mammalian Mnk1 and Mnk2) is upregulated systemically. Taken together, these results suggest that heterochromatin systemically mediates nuclear gene expression in muscle mitohormesis to promote longevity. This work contributes to a deeper understanding of epigenetic mechanisms by which the body adapts to
environmental challenges and may lead to better preventive/therapeutic strategies for age-related chronic diseases.

Akira, S., and Takeda, K. (2004). Toll-like receptor signalling. Nature reviews Immunology 4, 499-511.
Boyko, A., and Kovalchuk, I. (2011). Genome instability and epigenetic modification--heritable responses to environmental stress? Current opinion in plant biology 14, 260-266.
Bratic, A., and Larsson, N.G. (2013). The role of mitochondria in aging. The Journal of clinical investigation 123, 951-957.
Durieux, J., Wolff, S., and Dillin, A. (2011). The cell-non-autonomous nature of electron transport chain-mediated longevity. Cell 144, 79-91.
Hands, S., Proud, C., and Wyttenbach, A. (2009). mTOR’s role in ageing: protein synthesis or autophagy? AGING 1, 586-597.
Komeili, A., Wedaman, K.P., O'Shea, E.K., and Powers, T. (2000). Mechanism of metabolic control. Target of rapamycin signaling links nitrogen quality to the activity of the Rtg1 and Rtg3 transcription factors. The Journal of cell biology 151, 863-878.
Larson, K., Yan, S.J., Tsurumi, A., Liu, J., Zhou, J., Gaur, K., Guo, D., Eickbush, T.H., and Li, W.X. (2012). Heterochromatin formation promotes longevity and represses ribosomal RNA synthesis. PLoS Genet 8, e1002473.
Liu, L.P., Ni, J.Q., Shi, Y.D., Oakeley, E.J., and Sun, F.L. (2005a). Sex-specific role of Drosophila melanogaster HP1 in regulating chromatin structure and gene transcription. Nature genetics 37, 1361-1366.
Liu, X., Jiang, N., Hughes, B., Bigras, E., Shoubridge, E., and Hekimi, S. (2005b). Evolutionary conservation of the clk-1-dependent mechanism of longevity: loss of mclk1 increases cellular fitness and lifespan in mice. Genes & development 19, 2424-2434.
Liu, Z., and Butow, R.A. (2006). Mitochondrial retrograde signaling. Annual review of genetics 40, 159-185.
McColl, G., Killilea, D.W., Hubbard, A.E., Vantipalli, M.C., Melov, S., and Lithgow, G.J. (2008). Pharmacogenetic analysis of lithium-induced delayed aging in Caenorhabditis elegans. The Journal of biological chemistry 283, 350-357.
Mesquita, A., Weinberger, M., Silva, A., Sampaio-Marques, B., Almeida, B., Leao, C., Costa, V., Rodrigues, F., Burhans, W.C., and Ludovico, P. (2010). Caloric restriction or catalase inactivation extends yeast chronological lifespan by inducing H2O2 and superoxide dismutase activity. Proceedings of the National Academy of Sciences of the United States of America 107, 15123-15128.
Owusu-Ansah, E., Song, W., and Perrimon, N. (2013). Muscle Mitohormesis Promotes Longevity via Systemic Repression of Insulin Signaling. Cell 155, 699-712.
Pan, Y., Schroeder, E.A., Ocampo, A., Barrientos, A., and Shadel, G.S. (2011). Regulation of yeast chronological life span by TORC1 via adaptive mitochondrial ROS signaling. Cell metabolism 13, 668-678.
Pellegrino, M.W., Nargund, A.M., Kirienko, N.V., Gillis, R., Fiorese, C.J., and Haynes, C.M. (2014). Mitochondrial UPR-regulated innate immunity provides resistance to pathogen infection. Nature 516, 414-417.
Radak, Z., Zhao, Z., Koltai, E., Ohno, H., and Atalay, M. (2013). Oxygen consumption and usage during physical exercise: the balance between oxidative stress and ROS-dependent adaptive signaling. Antioxidants & redox signaling 18, 1208-1246.
Ristow, M., Zarse, K., Oberbach, A., Kloting, N., Birringer, M., Kiehntopf, M., Stumvoll, M., Kahn, C.R., and Bluher, M. (2009). Antioxidants prevent health-promoting effects of physical exercise in humans. Proceedings of the National Academy of Sciences of the United States of America 106, 8665-8670.
Scaffidi, P., and Misteli, T. (2006). Lamin A-dependent nuclear defects in human aging. Science 312, 1059-1063.
Scarpulla, R.C., Vega, R.B., and Kelly, D.P. (2012). Transcriptional integration of mitochondrial biogenesis. Trends in endocrinology and metabolism: TEM 23, 459-466.
Schroeder, E.A., Raimundo, N., and Shadel, G.S. (2013). Epigenetic silencing mediates mitochondria stress-induced longevity. Cell metabolism 17, 954-964.
Woo, D.K., and Shadel, G.S. (2011). Mitochondrial stress signals revise an old aging theory. Cell 144, 11-12.
Yan, S.J., Gu, Y., Li, W.X., and Fleming, R.J. (2004). Multiple signaling pathways and a selector protein sequentially regulate Drosophila wing development. Development 131, 285-298.
Yang, W., and Hekimi, S. (2010). A mitochondrial superoxide signal triggers increased longevity in Caenorhabditis elegans. PLoS biology 8, e1000556.
Yun, J., and Finkel, T. (2014). Mitohormesis. Cell metabolism 19, 757-766.
Zelenka, J., Dvorak, A., and Alan, L. (2015). L-Lactate Protects Skin Fibroblasts against Aging-Associated Mitochondrial Dysfunction via Mitohormesis. Oxidative medicine and cellular longevity 2015, 351698.