當細胞面對環境壓力(如養分缺乏、缺氧)等不利因素時，細胞能夠啟動許多促進環境適應的機制以確保存活。其中一種機制--自噬作用 (autophagy)為幫助細胞在不利環境下存活的重要反應。

 

Autophagy 意為細胞 ”自食” 的現象：Auto-源自於希臘文的”自 (self)”；phagy意指 ”吃 (eat)”。這種作用是細胞對於自己的胞內物質(大如胞器，小如蛋白質、脂質)進行回收分解的機制。如果將細胞比方成一座大城市，每日的車水馬龍的運作持續的造成城市各處堆積了許多垃圾或是損壞的物件。若不予以清除將很快對城市運作造成影響。自噬作用就像是城市的垃圾車、資源回收以及銷毀系統。如同大城市一般，細胞內可藉由自噬體 (autophagosome)－如同資源回收車一般來運送損壞或是多餘的胞器、不正常的的蛋白質或甚至是入侵的微生物。最終，自噬體將貨物(cargo)載往溶酶體 (lysosome)－細胞的垃圾處理場進行分解。這整個過程稱為「自噬作用」。此現象對於細胞生存是一個關鍵的機制。

 

過去二十多年的研究發現了自噬作用其實能夠透過某些辨認方式，選擇性的降解特定胞內物質，這樣的過程稱為選擇性自噬作用 (selective autophagy)。它扮演著胞內蛋白質與胞器恆定 (organellar homeostasis)、品質管控、或是胞內固有免疫 (intracellular innate immunity)中決定性的角色。包括粒線體、過氧化體 (peroxisome)、蛋白聚集體 (protein aggregates)、細菌、病毒或是半衰期長之蛋白質(long-lived proteins)等胞內結構都會被選擇性自噬清除。參與這項機制的基因若突變即可能影響這些胞內物質或入侵病原體的正常清除，而引起老化、神經系統退化疾病、癌症、或感染疾病。因此，了解選擇性細胞自噬的機制，即可能找到這些疾病的有效療法。

 

 

Macroautophagy (hereafter referred to as autophagy) is a catabolic pathway by which cells sequester unwanted or damaged cellular proteins or organelles through a double membrane structure called the autophagosome. This process is mediated by a set of evolutionarily conserved genes, the autophagy-related (ATG) genes, which function in nucleation of the autophagosomal membrane, elongation of the autophagic membrane, sequestration of cytoplasmic constituents, and lysosomal degradation of the sequestered contents.

 

Selective autophagy is a homeostatic quality control process that targets specific cytoplasmic components to autophagosomes for lysosomal destruction. Diverse cargos have been identified as substrates for selective autophagy, including mitochondria (mitophagy), peroxisomes (pexophagy), endoplasmic reticulum (ERophagy), and viruses (virophagy). Mitophagy is the major pathway by which eukaryotic cells eliminate damaged or unwanted mitochondria as damaged mitochondria release reactive oxygen species (ROS), leading to inflammasome activation, genotoxic stress, promotion of tumorigenesis and aging. Defects in mitophagy are implicated in neurodegenerative diseases such as Parkinson’s disease, Alzheimer disease, and age-related pathologies. Thus, the proper removal of mitochondria is essential for organismal health in diverse eukaryotic species.

The primary research focus of our laboratory is to understand the molecular regulation and biological functions of mitophagy. A fundamental question in the autophagy field remains how cargos such as mitochondria are selectively targeted for autophagic degradation. We will use series of genetic, cell biology, biochemical approaches to understand the mechanisms that confer substrate selectivity in mitophagy and investigate the pathological consequences of mitophagy dysfunction in diseases using model organisms such as C. elegans and mice. These studies may guide future efforts in developing therapeutic options against age-related and neurodegenerative diseases and pave the way for the development of new treatments for patients with diseases associated with mitochondrial dysfunction.