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

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.

Modeling alcohol-induced neurotoxicity using human induced pluripotent stem cell-derived three-dimensional cerebral organoids

“…Synthesized ATP by brain cell mitochondria fuels energy-dependent intracellular reactions (such as ion transport, vesicle release, and neurotransmitter biosynthesis and uptake), contributing to intracellular signaling, synaptic process, and brain function. Most defects of mitochondria are linked to neurodegenerative and metabolic diseases 123 . Previous findings from animal studies suggest that mitochondria appear to be a major target of ethanol toxicity in the brain.…”

Toxicity of Pioglitazone on Mitochondria Isolated from Brain and Heart: An Analysis for Probable Drug-Induced Neurotoxicity and Cardiotoxicity

“…Therefore, brain tissue needs mitochondria to maintain its normal function and energy consumption. Mitochondrial dysfunction in the brain is associated with neurodegenerative diseases [15,33,34]. In addition, energy consumption in the heart is similar to that of the brain.…”

“…Many compounds have caused mitochondrial toxicity and these organelles has become one of the research targets [13,14]. Brain and heart tissues depend on mitochondria for their high energy consumption and maintenance of their normal function [15,16]. Research has shown that mitochondria are one of the targets of PPARγ agonists [3,17,18].…”

Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease

“…Proteostasis is the maintenance of the proteome ensuring that all proteins are correctly folded, localized, and concentrated for their function. Mitostasis refers specifically to mitochondrial proteostasis [ 77 ]. Mitochondria possess both circular DNA and a transcription–translation machinery [ 78 ].…”