小宮 徹

Most mitochondrial proteins are nuclear-coded, synthesized on cytosolic free ribosomes as precursor with mitochondrial targeting signal (MTS), then transported to mitochondria. While extensive studies are made, some proteins are reported to be transported to dual destinations: mitochondria and the other compartment(s) in the cell. Among these we have clarified that P5, a member of protein disulfide isomerase family, is transported not only to the endoplasmic reticulum, but also to mitochondria. Now we study on how P5 is sorted to these two organells and on the putative mitochondrial targeting signal(s) in P5.

Defects in mitochondrial function cause not only a reduced energy production, but also an increased generation of reactive oxygen species (ROS), damage on mitochondrial morphology (in particular cristae), and if such defects are severe, damaged cells are destined to cell death. On the other hand, mitochondrial dysfunction has been suggested to be associated with numerous diseases, including cancer, diabetes, and neurodegenerative disease (Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, Amyotrophic Lateral Sclerosis, etc.). Despite its significance and extensive studies, in many cases, the relationships among oxidative stress-induced cell death, mitochondrial dysfunction, and causative effect(s) on diseases described above, are not well clarified so far.
Recently we have found that mitochondrial P5 suppresses the oxidative stress-induced cell death. Now we study the molecular mechanism(s) underlying the cell death suppression, and the relationships between intracelluar metabolism and cell death mechanisms.