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Macromolecular Crowding in Mitochondria.

Semen V Nesterov1, Vladimir N Uversky2

  • 1NRC "Kurchatov Institute", Moscow, Russia. semen.v.nesterov@phystech.edu.

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|September 26, 2025
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Summary

Cellular crowding significantly impacts mitochondrial structure and function. This high concentration of molecules within mitochondria influences their shape, enzyme complex formation, and overall physiological adaptations.

Keywords:
Enzyme supercomplexesIntermembrane spaceIntrinsically disordered proteinsMatrixMitochondrial functionMitochondrial shapeMitochondrial structureMitochondrial swelling

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Area of Science:

  • Biochemistry
  • Cell Biology
  • Mitochondrial Biology

Background:

  • Mitochondria are crucial organelles for cellular energy production.
  • The internal environment of mitochondria, particularly the matrix, is highly concentrated with macromolecules.
  • The role of this molecular crowding in mitochondrial function is often underestimated.

Purpose of the Study:

  • To review the multifaceted effects of macromolecular crowding on mitochondrial structure and function.
  • To elucidate how crowding influences mitochondrial shape, protein organization, and metabolic regulation.
  • To highlight the underappreciated role of crowding in mitochondrial physiology.

Main Methods:

  • Literature review and synthesis of existing data on mitochondrial crowding.
  • Analysis of the impact of excluded volume effects on mitochondrial matrix concentrations.
  • Examination of the relationship between protein concentration, lipid composition, and membrane curvature.

Main Results:

  • Mitochondrial matrix and inner membrane exhibit high macromolecular concentrations, while the intermembrane space is less crowded.
  • Crowding influences mitochondrial shape, the behavior of disordered protein domains, and responses to swelling.
  • Excluded volume effects lead to higher actual changes in ion and metabolite concentrations during swelling.
  • High protein density in the inner membrane drives cardiolipin enrichment to manage membrane deformations.
  • Crowding may act as a stimulus for the formation of mitochondrial enzyme supercomplexes.

Conclusions:

  • Mitochondrial structure is precisely adapted to high internal crowding conditions.
  • Macromolecular crowding is a fundamental regulatory factor in mitochondrial structure and function.
  • The significance of crowding in mitochondrial biology warrants greater attention in scientific research.