A team publishing in Aging Cell demonstrates that partial inhibition of pantothenate kinase reduces coenzyme A and iron-sulfur cluster levels, leading to HLH-30/TFEB activation and enhanced chaperone-mediated proteostasis in C. elegans and human cells. This mechanism improves stress resilience without lifespan extension, suggesting TFEB upregulation as a potential target for proteostasis disorders such as Alzheimer’s disease.
Key points
Partial inhibition of pantothenate kinase in C. elegans reduces CoA and ISC levels to activate HLH-30/TFEB–driven chaperone expression.
RNAi-mediated PanK reduction boosts proteostasis under heat and chemical stress in C. elegans and human cell models.
CoA supplementation reverses benefits, confirming that decreased CoA–ISC levels drive TFEB activation for enhanced protein folding.
Why it matters:
Targeting the PanK–CoA–ISC–TFEB axis offers a novel strategy to enhance proteostasis, potentially treating age-related neurodegenerative diseases.
Q&A
What is proteostasis?
How does TFEB regulate protein quality control?
Why use C. elegans as a model organism?
What role do iron-sulfur clusters play in this study?
Can this approach treat human neurodegenerative diseases?
Read full article
Academy
Proteostasis and Molecular Chaperones
Proteostasis refers to the cellular processes that maintain the health of the proteome by ensuring proteins fold correctly, are transported to the right locations, and that damaged or misfolded proteins are degraded. In living cells, thousands of proteins must adopt precise three-dimensional shapes to function properly. When the proteostasis network fails, misfolded proteins can accumulate, forming aggregates that damage cells and contribute to age-related diseases such as Alzheimer’s and Parkinson’s.
Molecular chaperones are specialized proteins that assist in the folding and unfolding of other proteins. They work by binding to unfolded or partially folded proteins, preventing incorrect interactions and guiding them into their proper structures. Key families of chaperones include heat shock proteins like HSP70 and HSP90, which are named for their induction under stress conditions such as elevated temperatures.
Key Roles of Molecular Chaperones:
- Prevent aggregation by shielding hydrophobic regions of unfolding proteins
- Assist in refolding of stress-denatured proteins
- Target irreversibly damaged proteins for degradation via the proteasome or autophagy
The regulation of chaperones is tightly controlled by stress-responsive transcription factors. One such factor is TFEB, which activates genes involved in lysosomal function and autophagy, and also upregulates certain chaperones. When activated by stress or changes in metabolism, TFEB moves into the cell nucleus to boost the expression of these proteostasis components.
Coenzyme A and Iron-Sulfur Clusters: Coenzyme A (CoA) is a small molecule essential for energy metabolism and fatty acid synthesis. It also contributes to the assembly of iron-sulfur clusters, which are cofactors for many proteins involved in electron transfer. Recent research shows that limiting the synthesis of CoA through partial inhibition of the enzyme pantothenate kinase reduces ISC levels, triggering a stress response mediated by TFEB. This response leads to increased production of chaperones, enhancing the cell’s ability to handle misfolded proteins and resist environmental stresses.
Model Systems in Proteostasis Research: Scientists commonly study proteostasis in the nematode C. elegans due to its simple anatomy and genetic tractability. In these worms, researchers use RNA interference to reduce enzyme levels and observe effects on protein aggregation, movement, and stress resistance. Findings in C. elegans can often be translated into human cell models, providing insight into conserved mechanisms that operate across species.
Future Directions: Research is exploring whether direct activation of TFEB or modulation of CoA metabolism can be applied to treat human diseases. Clinical trials will need to assess the safety, dosage, and effectiveness of such interventions. Understanding how different stress pathways converge on the proteostasis network will guide the development of more targeted therapies.
Practical Implications:
- Pharmacological activators of TFEB may boost chaperone levels and autophagy
- Genetic or dietary approaches that modulate coenzyme A and iron-sulfur cluster metabolism can indirectly trigger TFEB
- Small molecules that mimic chaperone function are under investigation as therapeutics for proteostasis diseases
Understanding the proteostasis network and molecular chaperones provides a foundation for developing therapies that maintain protein health, a cornerstone of healthy aging and longevity research.