Mitochondria and MICOS – function and modeling

Haym Benaroya

doi:10.1515/revneuro-2024-0004

Article

Mitochondria and MICOS – function and modeling

Haym Benaroya

Published/Copyright: February 19, 2024

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From the journal Reviews in the Neurosciences Volume 35 Issue 5

Abstract

An extensive review is presented on mitochondrial structure and function, mitochondrial proteins, the outer and inner membranes, cristae, the role of F₁F_O-ATP synthase, the mitochondrial contact site and cristae organizing system (MICOS), the sorting and assembly machinery morphology and function, and phospholipids, in particular cardiolipin. Aspects of mitochondrial regulation under physiological and pathological conditions are outlined, in particular the role of dysregulated MICOS protein subunit Mic60 in Parkinson’s disease, the relations between mitochondrial quality control and proteins, and mitochondria as signaling organelles. A mathematical modeling approach of cristae and MICOS using mechanical beam theory is introduced and outlined. The proposed modeling is based on the premise that an optimization framework can be used for a better understanding of critical mitochondrial function and also to better map certain experiments and clinical interventions.

Keywords: mitochondria; physiology; metabolism; MICOS; cristae; Mic60

Corresponding author: Haym Benaroya, Department of Mechanical and Aerospace Engineering, Rutgers University, 98 Brett Road, Piscataway, NJ 08854, USA, E-mail: benaroya@soe.rutgers.edu

Acknowledgments

The author extends his sincere gratitude to Dr. Maria E. Solesio, a faculty colleague in the Biology Department at Rutgers University, for reading the manuscript and providing valuable insights and recommendations. Of course, the author is solely responsible for the contents of the final manuscript.

While the papers referred to in this manuscript are key representatives of current knowledge and thinking, many other papers could not be included. This fact does not reflect on the importance of those papers. The author is grateful to his department and university for the scholarly environment and library support that provided the foundation for this study.

Research ethics: Not Applicable.
Author contributions: The author has accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: The author states no conflict of interest.
Research funding: None declared.
Data availability: Not applicable.

Glossary

Cofactors are organic molecules that primarily originate from vitamins and bind to enzymes functionalizing them to catalyze defined reactions (Singh and Mozzarelli 2009).
Dimers are polymers created by the bonding of two monomer molecules. Dimeric structures are those with two identical or similar units. Many proteins and enzymes are dimeric, with the advantage of correct and rapid assembly in the cell. Dimerization is the bonding of two molecules or ions (Mei et al. 2005; Paumard et al. 2002).
Dynamin and dynamin-like proteins are GTPases that have a role in membrane remodeling (Ferguson and De Camilli 2012).
GTPases are enzymes that hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP) and inorganic phosphate P_i, which function as molecular switches essential to extracellular signal transduction in cells (Belenguer and Pellegrini 2013).
Free Energy, also Gibbs or Helmholtz free energies, refer to the energy available to perform work at constant temperature, as constrained by the first law of thermodynamics. They are functions of internal energy, temperature above absolute zero, pressure, enthalpy, and entropy, which are mathematically related to each other. The free energy is used to determine whether a system, biological or otherwise, can change its state. Free energy theories have been developed as brain theories (Friston 2010).
Myosin, with actin, forms the contractile filaments of muscle cells and is involved in motion in other types of cells. It is a molecular motor transducing mgATP (chemical energy) into mechanical energy, generating force and movement (Cooper 2000).
Oligomers are morphologically periodic molecules of few repeating units that can be constituted by monomers. Oligomerization (OG) is the chemical conversion of a few monomers into macromolecules (Betaneli et al. 2012). It is critical to at least several processes affecting crista: (i) OG of the F₁F_O-ATP synthase (with cardiolipin) is needed for the stability of the respiratory chain supercomplexes (at the cristae tips), (ii) OG of OPA1 is required for normal cristae structure, and (iii) OG of Mic10 is essential for membrane bending generally and CJ formation specifically.
Phosphorylation is a type of regulation of protein functions by inducing conformational changes in protein–protein functional contact surfaces. Phosphorylation is the addition of a phosphoryl (PO₃) group to a molecule. For biological systems, phosphorylation is critical for cellular storage or release of energy using carrier molecules. In mitochondria, OxPhos of adenosine diphosphate (ADP) converts it into adenosine triphosphate (ATP), storing free energy as chemical energy for later use. Protein phosphorylation and dephosphorylation dominantly control most cellular processes and signaling pathways, including extracellular stimuli (Ohlmeier et al. 2010). This procedure is carried out for essentially all neuronal proteins, and it is a key mechanism of neuronal plasticity. Phosphorylation is one of the most common events in the post-translational regulation of protein function.
Proteases are enzymes involved in many biological functions, in particular proteolysis. This breaking down of proteins into smaller chains or individual amino acids is critical for the formation of new proteins. In this way, proteases regulate the fate, localization, and activity of many proteins; modulate protein–protein interactions; and create new bioactive molecules. Proteases process molecular signals that are necessary to cellular information management (Dou and Tan 2023).
Proteasomes are multi-subunit assemblies of proteases, large enzymatic protein complexes, which selectively degrade intracellular proteins, including transcription factors that regulate the cell cycle. Polymerization of ubiquitin, known to work in concert with the proteasome, serves as the main degradation signal in mammalian cells for numerous target proteins (Tanaka 2009). In summary, proteasomes are responsible for breaking down proteins in cells, while proteases are enzymes that specifically break down peptide bonds between amino acids in proteins.
Synthases are enzymes that catalyze the synthesis of a compound. The evolutionarily conserved proton-driven ATP synthase, a key enzyme of cell respiration embedded in the cristae membrane, is composed of two rotary motors/generators, the proton-driven F_O and the ATP-synthesizing F₁. F_O and F₁ are coupled via elastic torque transmission and function without relative slip (Junge and Nelson 2015).
Translocases are proteins that generally reside in membranes and assist in moving molecules across that membrane (Geissler et al. 2002).

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Received: 2024-01-10

Accepted: 2024-01-14

Published Online: 2024-02-19

Published in Print: 2024-07-26

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Articles in the same Issue

https://doi.org/10.1515/revneuro-2024-0004

Keywords for this article

mitochondria; physiology; metabolism; MICOS; cristae; Mic60