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. 2018 Apr 26:9:196.
doi: 10.3389/fendo.2018.00196. eCollection 2018.

Mitochondrial Chaperones in the Brain: Safeguarding Brain Health and Metabolism?

José Pedro Castro  1   2 , Kristina Wardelmann  2   3 , Tilman Grune  1   2   4   5 , André Kleinridders  2   3
Affiliations

Mitochondrial Chaperones in the Brain: Safeguarding Brain Health and Metabolism?

José Pedro Castro et al. Front Endocrinol (Lausanne). .

Abstract

The brain orchestrates organ function and regulates whole body metabolism by the concerted action of neurons and glia cells in the central nervous system. To do so, the brain has tremendously high energy consumption and relies mainly on glucose utilization and mitochondrial function in order to exert its function. As a consequence of high rate metabolism, mitochondria in the brain accumulate errors over time, such as mitochondrial DNA (mtDNA) mutations, reactive oxygen species, and misfolded and aggregated proteins. Thus, mitochondria need to employ specific mechanisms to avoid or ameliorate the rise of damaged proteins that contribute to aberrant mitochondrial function and oxidative stress. To maintain mitochondria homeostasis (mitostasis), cells evolved molecular chaperones that shuttle, refold, or in coordination with proteolytic systems, help to maintain a low steady-state level of misfolded/aggregated proteins. Their importance is exemplified by the occurrence of various brain diseases which exhibit reduced action of chaperones. Chaperone loss (expression and/or function) has been observed during aging, metabolic diseases such as type 2 diabetes and in neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD) or even Huntington's (HD) diseases, where the accumulation of damage proteins is evidenced. Within this perspective, we propose that proper brain function is maintained by the joint action of mitochondrial chaperones to ensure and maintain mitostasis contributing to brain health, and that upon failure, alter brain function which can cause metabolic diseases.

Keywords: brain; chaperones; insulin signaling; mitochondria homeostasis; mitochondrial dysfunction; neurodegeneration.

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Figures

Figure 1
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.
Figure 2
Figure 2
The mitochondrial chaperones localization. Due to the elevated mitochondrial activity in each compartment, it becomes necessary to employ mitochondrial chaperones to ensure proper function. The localization of several chaperones and co-chaperones and their association with several of their targets is shown. Each chaperone or co-chaperone is placed in different mitochondrial compartments such as outer membrane (OM), inner membrane (IM), intermembrane space (IMS), and the matrix according to their main function. From the cytosol to the OM, Hsp90 assists the delivery of to-be-imported proteins to the mitochondrial translocase Tom70. Within the IMS, several chaperones such as HtrA2 allow unfolded proteins to translocate from OM to the IM and avoid degradation. On the IM reside the electron transport chain (ETC) proteins, so there are several IM chaperones that have the ability to bind and guarantee proper folding and function to ETC complexes such as NDUFAF1 and FAD-dependent oxidoreductase-containing domain 1, which bind to NADH:ubiquinone oxidoreductase (complex I). Moreover, COX17p binds to cytochrome C oxidase (complex IV) and helps with its assembly. It is however on the matrix that most of the mitochondrial chaperones or co-chaperones are localized. For example, the chaperone heat shock protein 60 cooperates with its co-chaperone Hsp10 in order to promote correct protein folding. The mtHsp70 and its co-chaperone HSC20 help to promote protein folding and avoid protein aggregation, a detrimental feature that leads to mitochondrial dysfunction. Other chaperones exhibit more than one task. This is the case of DNAJA3, a chaperone that avoids complex I aggregation but is also able to assist mitochondrial DNA maintenance. Other crucial processes such as mitochondrial protein synthesis rely on a proper mitoribosome assembly, a task that is employed by the RNA chaperone ERAL1. In order to keep mitochondria homeostasis—besides correct (re)folding and synthesis—protein degradation is also mandatory. To this effect, mitochondria have proteases such ClpP and ClpX that play a role in degrading no longer required, misfolded, or damaged proteins, and ClpB mainly as a chaperonin and a disaggregase. The conformational display of each protein or complex and binding layout is merely illustrative.
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