粒線體：抗發炎藥之標的

Mitochondria: Target for the Develop of Anti-inflammatory Drugs

老年病，尤其慢性發炎隨人口老化而增加，這除了影響健康，對家庭及社會更是重擔，因之開發抗發炎藥，甚為重要。在2014年，有26篇以上有關抗發炎、抗老化、抗氧化植物藥回顧性論文發表，可見從植物藥找新藥的重要性。由粒線體製造的自由基或活性氧物質(ROS)是慢性發炎及老化的原因，所以瞭解粒線體的功能有助於抗發炎藥物的研發。粒線體是共生於細胞內另一種細菌演化而成的，它具有自己的DNA；粒線體是傳自母系的，而已用以追蹤現代人的來源。細胞核及粒線體DNA所編譯的蛋白質影響彼此的功能。
粒線體與內質網形成的膜(MAMs)緊密聯結而相互作用。粒線體不斷進行氧化還原反應、增生、降解、分裂與融合及傳送到細胞內各處。氧化還原反應由不同內生性及從飲食得到的物質來調控。粒線體融合使代謝產物、蛋白質、DNA充分接觸。粒線體分裂將受傷粒線體隔離，再以粒線體自噬清除之。細胞質的鈣是由內質網經由鈣單向運載蛋白及肌醇三磷酸受體(IP3R)傳送到粒線體。IP3R透過葡萄糖調控蛋白75(Grp-75)與MAMs上mTORC相互作用來調控粒線體外膜的陰離子通道(VDAC)，參與代謝物、鈣等離子的交換、也抑制內質網壓力與細胞凋亡。mTORC1控制粒線體自噬，粒線體活性及製造。粒線體釋放的細胞色素C可阻斷鈣離子所誘導IP3R的鈣離子回收，使鈣離子從ER和粒線體的釋放量增加。VDAC與己糖激酶2（HK2）結合後、與B細胞淋巴細胞蛋白2（Bcl2）相互作用、減少鈣離子從ER進入粒線體，進而減少ROS產生。IP3R可與PML-NBs形成複合體參與鈣和細胞凋亡的調控。磷酸酶及張力蛋白同源物（PTEN）可拮抗Akt所誘導的對IP3R的抑制及鈣離子從ER的釋放。PINK1（PTEN induced putative kinase 1）藉由聯結parkin及似NIP3的粒線體外膜蛋白(NIP3-like protein X)的參與，而引起粒線體自噬(mitophagy)。內質網的NLRP3發炎體被ROS及鈣活化而移動到粒線體。癌細胞進行耗氧醣解，因之粒線體之丙酮去氫酶與癌的發生有關。更已知粒線體DNA突變引起癌細胞之轉移及對抗癌藥有抗藥性。在神經細胞粒線體內外膜交接處的運輸蛋白運送膽固醇及紫質至粒線體內以製造神經固醇。粒線體內膜的ATP結合板面(ABC)從事胞質與胞核的互動，ABC的突變引起一些遺傳性疾病。針對上述粒線體複雜的功能及相關調控系統以研發抗發炎藥、抗氧化及抗老化藥物，其不同標的、方法及合理性在文中加予討論。

In 2014, more than 26 review articles related to antiaging, anti-inflammatory and antioxidative effects of herbal drugs appeared. Free radicals or reactive oxygen species (ROS) are majorly produced by mitochondria (Mt) and malfunction of Mt has been hypothesized as the fundamental factor causing the chronic inflammation and aging. Mt is an endomicrobiota, rickettsia like α-purple bacteria, an anerobe which engulfed the bacteria that using oxygen and sugar to keep the energy in ATP. The proteins encoded by nuclear and Mt DNA affected each other’s functions. Mt is well interacted with endoplasmic reticulum (ER) on mitochondriaassociated ER membranes (MAMs). Mt process redoxidation, biogenesis, degradation, fission, fusion, and transport along the cell extremity continuously. The fusion mixed the metabolites, proteins, and mtDNA, while fission segregated the damaged component of Mt and rearranged Mt by mitophagy, the selective degradation of mitochondria by autophagy. Calcium (Ca2+) is transported from ER to Mt through permeability transition pore by Mt Ca2+ uniporter, and transmembrane inositol 1, 4, 5-triphosphate receptor (IP3R). IP3R interacted with mTORC2 at MAM to regulate voltage-dependent anion channel (VDAC) on outer Mt membrane through glucose-regulated protein 75, to perform the exchange of metabolites and ions, and also involved in the inhibition of ER stress and apoptosis. while, mTORC1 controls mitophagy, mitochondrial activity and biogenesis. The cytochrome C released from Mt blocked the Ca2+-induced IP3R inhibition, and then increased Ca2+ release from ER and cytochrome C from Mt. VDAC interacted with hexokinase 2 (HK2) and B-cell lymphocytic protein-2 (Bcl2) decreased the entrance of Ca2+ from ER to Mt, then decreased ROS production. Promyelocytic leukemia nuclear bodies form a complex with IP3R, which is involved in Ca2+ and apoptosis regulation. Phophatase and tensin homolog deleted on chromosome 10 (PTEN) antagonized Akt-induced IP3R inhibition and Ca2+ release from ER. PTEN-induced putative kinase 1 (PINK1) recruits parkin, then selectively degrades the microtube-associated protein light chain 3 alpha. Mitophagy is the process to deplete damaged Mt by lysosome which control the function of MAMs, Ca2+ uptake, bioenergetics of Mt, and apoptosis through IP3R, HK2 and phosphofurin acidic cluster sorting protein 2. NLRP3 inflammasomes located in ER are activated and migrated to MAMs by ROS. Stimulator of interferon genes with retinoic acid-induced gene-like helicase stabilized the MAMs, but activated type I interferon production. The activity of pyruvate dehydrogenase phosphatase is related to carcinogenesis. The point mutation of mtDNA promotes cancer metastases and drug resistance to some anticancer agents. The ATP binding cassette (ABC) is located in inner Mt and nucleotide binding domain. ABC regulates the communication between nuclear and cytosol. The mutation of ABC protein B7, a cytosolic-nuclear iron-sulfur protein, caused the sideroblastic anemia and cerebellar ataxia. The targets methods, and rational for the development of antiaging, anti-oxidant, or anti-inflammatory drugs are mentioned in the text.