Limiting One Protein Maintenance Pathway Enhances Another

Enhancing Chaperone Function Leads to Stress Protection

In a recent study published in Aging Cell, researchers investigated the relationship between coenzyme A (CoA) metabolism and protein maintenance pathways, revealing promising insights into enhancing cellular stress resistance through modulation of pantothenate kinase (PanK) levels.

Maintaining Protein Function

Proteostasis is essential for cellular health, relying on a network of chaperones and co-chaperones that manage protein folding, unfolding, and the degradation of misfolded proteins [1]. Stress responses modulate this network via transcription factors that regulate proteostasis-related genes [2].

CoA is a vital cofactor involved in various biochemical processes, including mitochondrial energy production, steroid synthesis, and protein management. To synthesize CoA, the body utilizes PanK, which acts as a key regulatory bottleneck in its production [3]. Deficiencies in PanK can lead to severe neurological disorders due to its critical role in cellular function [4].

Moreover, CoA is responsible for producing iron and sulfur clusters (ISCs) necessary for cellular respiration and metabolism [5]. However, disruptions in ISC transport can lead to various diseases [6].

This study highlights the connection between CoA, ISCs, and the common transcription factor TFEB, known as HLH-30 in C. elegans.

A Possible Benefit of Limitation

Contrary to expectations, the full depletion of PanK in C. elegans resulted in conditions that mimic severe human diseases [7]. Interestingly, halving its production did not shorten the lifespan of these worms. Instead, in worms with a genetic mutation causing PolyQ expansion (a disorder of proteostasis), reduced PanK levels resulted in:

  • Fewer protein aggregates in muscle tissue.
  • Enhanced muscle activity and mobility.

This phenomenon was observed specifically in worms subjected to RNA interference (RNAi) targeting PanK expression, highlighting the complexity of genetic interactions in proteostasis mechanisms.

Effects on Stress Response

Further experiments involving a temperature-sensitive muscle protein mutation showed that decreased PanK improved movement at elevated temperatures, indicating robust proteostasis mechanisms in action. In subsequent tests with insulin proteins, worms exhibiting chronic stress demonstrated impaired protein handling, yet those with decreased PanK exhibited better processing and folding of insulin, leading to improved cellular outcomes.

Research findings demonstrated that worms with reduced PanK levels exhibited enhanced stress tolerance during both chemical insults and heat shock conditions, suggesting a connection between CoA depletion and stress resilience.

Protein Chaperones to the Rescue

To unravel the underlying mechanisms, researchers investigated mitochondrial function and identified that reducing CoA and ISCs through PanK suppression led to significant improvements in proteostasis. Notably, these improvements were aligned with increased chaperone-mediated protein folding, diverging from traditional pathways of proteasomal or lysosomal degradation.

Notably, a total of 13 chaperones that improved survival under heat shock conditions were identified, with 10 of these being directly associated with HLH-30/TFEB, reinforcing the contribution of this transcription factor in protein maintenance.

The Role of TFEB

The findings confirm that reduced CoA and ISCs resulting from PanK inhibition increase HLH-30/TFEB activity, promoting beneficial responses in protein chaperones. While the effects are promising, it is important to note that the study did not observe significant lifespan extensions in the worms, suggesting that further research is necessary. Future studies aiming to directly boost chaperone levels may reveal effective therapeutic strategies for combating proteostasis disorders such as Alzheimer's and Parkinson's.

Conclusion

The study highlights a paradoxical relationship between PanK, CoA levels, and cellular stress response, suggesting that limiting one pathway may enhance another in maintaining proteostasis. The direct implications for human health are profound, as enhancing chaperone function could be a viable strategy to combat age-related diseases and improve overall cellular resilience.

Literature

  1. Jayaraj, G. G., Hipp, M. S., & Hartl, F. U. (2020). Functional modules of the proteostasis network. Cold Spring Harbor Perspectives in Biology, 12(1), a033951.
  2. Pessa, J. C., Joutsen, J., & Sistonen, L. (2024). Transcriptional reprogramming at the intersection of the heat shock response and proteostasis. Molecular Cell, 84(1), 80-93.
  3. Robishaw, J. D., & Neely, J. R. (1985). Coenzyme A metabolism. American Journal of Physiology-Endocrinology and Metabolism, 248(1), E1-E9.
  4. Gregory, A., & Hayflick, S. J. (2017). Pantothenate kinase-associated neurodegeneration.
  5. Paul, V. D., & Lill, R. (2015). Biogenesis of cytosolic and nuclear iron–sulfur proteins and their role in genome stability. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 1853(6), 1528-1539.
  6. Maio, N., & Rouault, T. A. (2020). Outlining the complex pathway of mammalian Fe-S cluster biogenesis. Trends in Biochemical Sciences, 45(5), 411-426.
  7. Samuelson, A. V., Carr, C. E., & Ruvkun, G. (2007). Gene activities that mediate increased lifespan of C. elegans insulin-like signaling mutants. Genes & Development, 21(22), 2976-2994.