Workshop
「Slow-aging工学の展開」
講演概要
Mitochondrial unfolded-protein-response as a cellular defense mechanism in aging
Rei-Cheng Yang, M.D.; Ph.D.
All good things come to an end, including life. Aging is the natural process of accruing maturity with passage of time, during which deteriorative processes that constitute natural course of death occurs. Among the theories of aging or senescence, accumulation of ROS inducing denature of protein in mitochondria is the most convincing one. Mitochondria are well known to produce energy as well as deal with ROS. Accumulation of ROS leads to a stressed situation and increase the pool of unfolded and misfolded proteins in mitochondria. These proteins can culminate in wild-ranging changes in nuclear gene expression via retrograde signaling from the mitochondria to the nucleus, so called mitochondria-nuclear communication (MINCO). The mitochondrial unfolded protein response (mt-UPR) is one of the MINCO responses, that activates transcription of nuclear-encoded mitochondrial chaperone genes (hsp60/ 10) and proteases (mtDnaJ and ClpP) to promote protein homeostasis within the organelle. Therefore, the mt-UPR is the most important protein quality control system in oxidative stress- related pathology. From our previous studies in a cecal-ligation-and-puncture (CLP) sepsis model, we have found that content of ATP production decreased, membrane potential decreased, apoptosis increased, etc. Nevertheless, we also found most of the adverse effects could be reversed by previous overproduction of chaperone proteins. In addition, the MINCO seems failure by the fact that expression of IF-1 (mitochondrial ATPase inhibitory protein-1) is not provoked despite of the bioenergetic failure in late stage of sepsis. Furthermore, the results showed that the response could be induced 3 hours after sepsis induction but then these chaperone proteins decreased along with the progress of sepsis. However, the result could also be reversed by preconditioning synthesis of Hsps and the mortality was significantly decreased. These results encourage us to further investigate whether effective mt-UPR may play critical role in slowing the process of aging by its protein quality control mechanism.