Autophagy, from Greek “self-eating,” is a process in which a cell degrades its own proteins and damaged organelles and reuses the building blocks. When starvation or oxidative stress occurs, this pathway is strongly activated to secure energy and raw materials. Dr. Ohsumi used budding yeast to collect many mutants that could not perform autophagy and identified a set of ATG (autophagy-related) genes. Thanks to this, scientists could follow where the membrane that forms the autophagosome originates and how the finished vesicle reaches the lysosome. Because autophagy clears protein aggregates such as amyloid, it offers clues to slowing Alzheimer’s and Parkinson’s diseases. It also functions as a “cellular immune system” by engulfing and destroying invading bacteria and viruses. Some cancer cells exploit autophagy to survive in nutrient-poor environments, so drugs that fine-tune this pathway are under development. Dr. Ohsumi’s work provided researchers worldwide with the blueprint of the cell’s recycling plant. His approach highlights the importance of model organisms like yeast, familiar even from high-school biology, and shows how simple systems can yield big discoveries. Understanding autophagy teaches us how life smartly manages limited resources.

Autophagy comprises the sequestration of cytoplasmic material by a double-membrane autophagosome, followed by fusion with the lysosome/vacuole and enzymatic degradation. In 1992, Yoshinori Ohsumi visualized autophagic bodies inside the vacuole of protease-deficient yeast by light microscopy, creating a system that allowed genetic manipulation of the pathway. His 1993 screen identified 15 ATG genes, laying the foundation for subsequent molecular dissection. He demonstrated that the Atg1–Atg13–Atg17 complex is regulated by TOR kinase signaling and activates autophagy upon nutrient deprivation. Ohsumi also proved that two ubiquitin-like conjugation systems, Atg12–Atg5–Atg16 and Atg8–PE, are indispensable for autophagosome membrane expansion and that these mechanisms are conserved from yeast to mammals. These insights revealed that autophagy is not merely bulk degradation but includes specialized forms such as mitophagy and xenophagy. Fundamental discoveries have spurred drug-discovery efforts, including the use of the mTOR inhibitor rapamycin and Atg4 inhibitors for cancer and neurodegenerative diseases. Knockout mouse studies showed that neonates lacking Atg5 die during early starvation and that neuron-specific Atg7 deficiency causes movement disorders, proving the pathway’s essential role in homeostasis. Conversely, excessive autophagy may drive muscle wasting and heart failure, highlighting the need to understand fine-tuned regulation in vivo. Ohsumi’s work bridges organelle biology, immunology, and aging research, opening a new horizon in life sciences with “self-digestion” as a core concept. Current studies combine CRISPR/Cas9 and super-resolution microscopy for spatiotemporal mapping of ATG factors, as well as systems biology modeling. Collectively, these efforts are reshaping our understanding of pathophysiology and therapeutic strategies from both cell-autonomous and tissue-level perspectives.

Ohsumi’s comprehensive identification of autophagy-deficient yeast mutants delineated the core machinery comprising the Atg1 kinase complex, PI3K complex I/II, and two ubiquitin-like conjugation cascades. The Atg1-Atg13-Atg17-29-31 complex toggles membrane nucleation via TORC1-dependent phosphorylation sites and, upon dephosphorylation, is recruited to the phagophore assembly site (PAS). Dynamic studies of Atg9 cycling vesicles suggested that Atg9 supplies lipid flux through scramblase activity, and its PAS localization depends on scaffolding by the Atg11 family. Ohsumi further reported that the Atg12–Atg5–Atg16 complex exhibits E3-like activity, and local enrichment of Atg8-PE drives autophagosomal hemifusion and curvature sensing. Conservation from yeast to mouse allowed verification of diverse phenotypes—neonatal lethality, neurodegeneration, immune deficiencies—in ATG knockout models, underscoring intricate regulation by post-translational modification networks. In parallel with rapamycin sensitivity assays, his group quantified functional differences between ATG-dependent and PI3K inhibitor-induced autophagy using 3-MA and wortmannin. Recent high-resolution structures of Atg13/ULK1 show that release from the mTORC1-Ragulator complex is the rate-limiting step in PAS assembly, corroborating Ohsumi’s proposed “control point model.” Autophagy integrates at multiple levels—muscle quality control, mitochondrial clearance during erythropoiesis, inflammasome regulation—with functional redundancy and selectivity of ATG factors coordinated by post-translational cascades. In tumor microenvironments, ROS-induced Nrf2–p62 positive feedback promotes Atg7-dependent xenophagy, contributing to drug resistance. Immunologically, cGAS–STING–TBK1 signaling cross-regulates autophagosome formation, offering new insight into viral dsDNA responses and autoimmunity etiology. Clinically, Hsp90 inhibitors and HDAC inhibitors modulate autophagy signaling and are being evaluated in phase I/II trials to enhance combination chemotherapy synergy. These conceptual and technical breakthroughs, initiated by Ohsumi’s work, have decisively driven a paradigm shift in cell dynamics research.