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 neuro de-generative 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, 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.
2. Introduction
• The brain co ordinate organ function and regulates whole body metabolism by the
concerted action of neurons and glia cells in the central nervous system
• Brain needs high energy consumption and depends mainly on glucose utilization and
mitochondrial function for its functions.
• High rate metabolism of mitochondria in the brain leads to mitochondrial DNA (mtDNA)
mutations, reactive oxygen species, and misfolded and aggregated proteins.
• Mitochondria need to employ chaperones to avoid or ameliorate the rise of damaged
proteins that contribute to aberrant mitochondrial function and oxidative stress
• Brain function is maintained by the joint action of mitochondrial chaperones to maintain
mitostasis contributing to brain health.
• Failure of chaperones can alter brain function and can cause metabolic diseases.
3. CHAPERONES
• Chaperones are proteins that interact with unfolded, partially folded or improperly
folded polypeptides facilitating correct folding pathways or providing
microenvironments in which folding can occur.
• Location-mitochondria and ER of eukaryotes
• Maintain mitochondria homeostasis (mitostasis) and a low steady-state level of
misfolded/aggregated proteins.
• 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.
4. MITOCHONDRIA IMPACT BRAIN
FUNCTION
• Mitochondria metabolize the end product of glycolysis pyruvate, as well as ketone
bodies, to generate ATP.
• Aberrant mitochondria in the brain leads insulin resistance (IR) and to metabolic
diseases such as metabolic syndrome and type 2 diabetes (T2D)as well as aging.
• Misfolding of proteins or protein aggregation decreases mitochondrial activity,
causes oxidative stress and neurodegenerative diseases
• Mitochondrial Unfolded Protein Response (UPRmt)- a signalling pathway where
the abundance of misfolded mitochondrial proteins causes a nuclear signal to re-
establish protein homeostasis by inducing mitochondrial chaperones and
proteases to re-instate protein homeostasis within mitochondria.
7. ROLE OF CHAPERONE IN BRAIN
1. CHAPERONE DEPENDENT MITOSTASIS
2. THE SPECIAL CASE OF CHAPERONES AS REGULATORS OF CENTRAL
INSULIN SENSITIVITY
8. Chaperone–Dependent Mitostasis
• Chaperone action or in combination with co-chaperones that regulate their
interaction and activity with client proteins.
• mtHsp70 with co-chaperones such as HSC20, which enables mtHsp90 peptide
binding activity
• DNAJA3 (also namedTID1) that helps to prevent complex I aggregation and takes
part in mtDNA maintenance.
• Mdj1p involved in protein folding and also in mitochondrial biogenesis.
10. Importance of Insulin Sensitivity in the
Brain
• Insulin signaling in the brain regulate food intake and energy expenditure
but also improves cognitive function
• Insulin Resistance(IR) leads hyperphagia and obesity also
neurodegenerative diseases and neurological alterations such as mood
disorders
• Protein homeostasis and functional insulin signaling in the brain regulated
by cluster of stress proteins like Hsps and proteases(UPRmt)
• Role of Hsps –Repair protein damage and denaturation
11. Mitochondrial ChaperonesAs Regulators
of Brain Insulin Sensitivity
• Hsp70 family are the most prominent and well characterized stress proteins belong in the
various compartments of the cell.
• The inducible Hsp70 is ubiquitously expressed and is a highly conserved chaperone,
localized in the cytosol and induced by heat, oxidative stress or by changes in the pH.
• highly abundant and easily producible therapeutic target .
• Chaperone Hsp70 could be a potential new treatment for diabetes
• The extension of life span was achieved in Drosophila melanogaster and c. elegans by the
upregulation of Hsp70 via heat shock.
• Hsp90 maintain mitostasis by using its antioxidant capacity as well as the regulation of
mitophagy and mitochondrial dynamics.
• Reduced expression of Hsp90 has been linked to pathologies like Parkinson’s disease.
12. CONCLUSION
1) The presentation gave an overview of the chaperone proteins present in the organelles like
mitochondria and its various functions.
2) The study shows that the brain functions are maintained by a combined action of mitochondrial
chaperones maintaining mitostasis
3) MitochondrialChaperones are important in mitochondrial protein synthesis, protein folding,
energy production, etc
4) Mitostasis balance assist in brain health as well as prevents metabolic diseases linked to it.
5) Brain mitochondrial dysfunction results from disruption of mitochondrial chaperones network
thereby affecting brain insulin sensitivity.
6) These changes in brain metabolism finally reflect on aging and age related metabolic disorders.
7) In the upcoming future more research needs to be focused on chaperonic interactions, their activity
and alterations in brain functions and metabolism.
8) Studying mitochondrial chaperones functions would definitely improve neuronal health and
metabolism contributing to healthy aging in the near future.
