Figure 1.

The central role of chaperones in mitochondrial protein homeostasis. In the brain, mitochondria are kept under optimal functional conditions by employing two major mitochondria homeostasis (mitostasis) processes, (re)folding and degradation. Under tight regulation and concerted action these processes avoid the accumulation of different types of damage such as ROS, mitochondrial DNA mutations or misfolded/aggregated proteins known to promote mitochondrial dysfunction. Moreover, a mild increase in the level of misfolded proteins triggers the UPRmt response that quickly helps to establish mitostasis. In the brain, under these conditions, chaperones promote mitochondrial function keeping the brain and whole body in an insulin sensitive state. In contrast, if refolding or degradation processes become impaired due to the loss of mitochondrial chaperones expression or activity this results in misfolded and aggregated protein accumulation. This detrimental state leads to oxidative stress that can affect mitochondrial function and thus brain metabolism. A likely consequence is the resistance to insulin not only initially in the brain but also to peripheral tissues later on, abrogating whole body metabolic homeostasis. This metabolic shift is a likely percursor for aging, neurodegenerative and metabolic diseases progression, and establishment. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License.