Our Subject

1, Analyses of “alternative macroautophagy”

     Autophagy (macroautophagy) has been one of the areas that has recently attracted considerable attention.  Autophagy is the mechanism involved in bulk degradation of cellular constituents that has an integral role in various physiological events, including cell survival despite lack of nutrients, removal of infectious agents, development, and programmed cell death.  It is currently thought that ATG5 and ATG7 are essential genes for macroautophagy, and that modification of ATG8 homologues (such as LC3) is the best indicator of the occurrence of macroautophagy.  Therefore, ATG5-/- and ATG7-/- cells are studied as macroautophagy-deficient cells, and lack of LC3 modification is interpreted as the absence of macroautophagy.  Recently, however, we provide evidence that mammalian macroautophagy not only involves an ATG5/ATG7-dependent conventional pathway, but also an ATG5/ATG7-independent alternate pathway.  In addition, we also provide evidence that alternate macroautophagy is not associated with modification of LC3, indicating that LC3 modification only identifies part of macroautophagy.  Furthermore, we developed a procedure to monitor this alternate process of macroautophagy and found that Beclin-1 and ULK1 play a crucial role.  In vivo, we demonstrated that this alternate process had a role in the clearance of mitochondria during erythrocyte maturation.  These findings indicate the existence of a novel macroautophagy pathway with physiological relevance.  Our final goal is to understand the physiological and pathological roles of “alternative macroautophagy” in humans.                       


2, Molecular mechanisms of programmed cell death

  Programmed cell death is the essential mechanisms for selective elimination of cells.  It plays an integral part in a variety of biological events, including morphogenesis and removal of harmful cells.  Dysfunction of programmed cell death leads to various diseases, including cancer and autoimmune diseases.  Previously, apoptosis is considered as the only form of programmed cell death.  Recent studies, however, have provided evidence that there is another mechanism of programmed cell death called non-apoptotic cell death.  Therefore, in order to understand the role of cell death in multicellular organisms, it would be required to elucidate all the molecular mechanisms of cell death, and to analyze knockout mice in which each death mechanisms are disrupted.  Our final goal is to understand the role of programmed cell death in humans.     

  A, Analysis of apoptosis mechanism

  B, Analysis of non-apoptotic cell death (autophagic cell death, necrosis)

  C, Physiological role of cell death in mammals

  D, Pathological role of cell death in mammals


3, Analysis of mitochondrial diseases

     Mitochondria play an essential role in both cell survival and cell death.  In both cell function, mitochondrial membrane permeability is crucial.  Therefore, we are focusing on channel proteins located on mitochondrial membrane.  We are also focusing on mitochondrial diseases.

     The mitochondrial connection to neurodegenerative diseases especially Parkinson’s disease, began almost 20 years ago, when it was discovered that MPTP, a mitochondria toxic agent, induces Parkinson’s disease.  Recently, some of the genes associated with familial Parkinson’s disease also implicate mitochondria in disease pathogenesis.  We are aiming to elucidate the cause of Parkinson’s disease from the mitochondrial dysfunction.