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From CellBiology

Mitofusin 2 (MFN2)

Introduction

Structure of Mitochondria
Fission and fusion of mitochodria

Mitochondria exist as tubular networks or in filamentous meshwork arrangements within cells [1] . The morphology of these organelles change from cell to cell depending on energy requirements, cell type, cell location and other factors such as pathological states. The way in which the morphology of this organelle can be altered in different cell types as in any cell is through the process of fission and fusion, which is under the control of a range of different pro-fusion and pro-fission proteins associated with the outer and inner membrane of mitochondria as well as with other organelles, such as the endoplasmic reticulum[2][3] (Fission & Fusion). One such protein found in humans is Mitofusin-2 (MFN2) which is a pro-fusion transmembrane protein found ubiquitously but in differing levels throughout different tissue cells in humans. Recent research has indicated that the roles of MFN2 go beyond that of influencing mitochondrial morphology and relate to its differing structure to that of similar mitochondrial proteins, for example Mitofusin-1 (MFN1).

Protein Structure

"Core" Mitochondrial-shaping Protein Shape

Mitofusin-1 (MFN1) and MFN2 share very similar homology (60%)[4] and topology, however there are a few key differences between the structure of these two proteins that suggests a role for MFN2 beyond its function of promoting fusion of mitochondria. Both MFN1 and MFN2 have 'an N-terminal GTPase domain, two transmembrane domains spanning the outer mitochondrial membrane and two regions crucial for protein-protein interaction'[5]. The regions crucial for protein-protein interaction are coiled coil structures found flanking the transmembrane domains at the C-terminus, and MFN2 is also known to contain a domain continuous with the N-terminus GTPase which is responsible for binding and sequestering p21Ras[6]. MFN2 also has a higher affinity for GTP in its GTPase domain than that of MFN1 while having a lower GTPase activity than MFN1. MFN1 interacts with an inner-mitochondrial membrane protien, OPA1, to induce fusion of mitochondria, whereas MFN2 stimulates mitochondrial fusion independent of OPA1. These differences in structure are related to other cellular interactions for MFN2 which may or may not be associated to its role as a mitochondria-shaping protein[7].

Cellular Function/Roles

As current knowledge of structure and function of MFN2 progresses, it is becoming clearer and clearer that MFN2 plays a key role in a diverse range of cellular processes and that disruption of MFN2 function has a detrimental effect on cell physiology. These functions include:

Regulating mitochondria shape

Regulating Mitochondrial Metabolism

  • MFN2 expression is crucial in mitochondrial metabolism through the maintenance of the mitochondrial network architecture, and reduced MFN2 expression may explain some of the metabolic alterations associated with obesity[10]. Data has been shown that partial abolition of MFN2 modifies mitochondrial metablism in cells, perhaps indicating a role in the maintainance of maximal activity of respiratory chain complexes[11]

Apoptosis

  • Briefly, in the process of apoptosis, BAX protein accumulation in mitochondria precedes caspase activation and extensive mitchondrial fragmentation (fission). MFN2, aside from its pro-fusion properties, is involved in preventing the BAX proteins from translocating on mitochondria, thus regulating the activation of elements which are involved in the release of cytochrome C and apoptosis[12][13]

.

Shape of other organelles

  • MFN2 has been shown to localize not only on the mitochondrial membrane but also on the membrane of the endoplasmic reticulum (ER) of mammalian cells at sites called mitochondria-associated membranes (MAMs). The current understanding of the function of MFN2 on ER is to tether the ER to the mitochondria by interracting with MFN1 snd MFN2 on the mitochondria, as well as playing a role in maintaining the morphology of the ER. This is significant because of the importance of juxtaposition of the mitochondria and ER in the cellular processes of lipid biosynthesis, Ca2+ signalling and apoptosis. 'One of the main functions of Ca2+ uptake by mitochondria is to activate intramitochondrial dehydrogenases, leading to activation of mitochondrial metabolism and energy production' therefore close association between mitochondria and ER is conducive to faster signalling. [14][15]

Progression through cell cycle

  • The role of MFN2 in relation to the cell cycle links back to its RAS-binding domain. MFN2 physically sequesters RAS, which is a protein involved in cellular signal transduction, and its sequestration leads to inhibition of RAS signalling pathways and eventuates in the cell cycle being stopped at G0/G1[16].

Abnormalities/Diseases associated with MFN2

  • OMIM Database Entry on Mitofusin 2 - MITOFUSIN 2
  • Charcot-Marie-Tooth type 2A (CMT2A)
    • 'In CMT2A, the loss of sensory and motor axons eventually results in the degeneration of the neurons themselves. Mutations in MFN2 account for ~20% of CMT2 cases, making this the most prevalent axonal form of CMT. Most MFN2 mutations in CMT2A cluster within the GTPase and the RAS-binding domains and are missense mutations[17]. The mutations in the GTPase and Ras-binding domains of MFN2 directly effect morphology and tethering of the ER to mitochondria, and this could underly the neurodegenerative effects seen in CMT2A[18]
  • Type 2 Diabetes Mellitus (and obesity)
    • It has been observed that in individuals suffering from obesity and related type 2 diabetes have much lower levels of MFN2 espression in skeletal (as high as 40%) and that these patients also exhibit smaller mitochondria. This could relate to the activity of MFN2 on cellular metabolism and respiration[19]
  • Vascular Proliferative Diseases
    • Hyperproliferating smooth muscle cells, found in the walls of blood vessels in diseases like atherosclerosis, have been found to have downregulated MFN2 levels, which may relate to MFN2's role in the progression of the cell cycle (see above)[20]

Glossary

  • Atherosclerosis - A disease caused by the build-up of fatty plaques on the inner lining of arterial blood vessels, narrowing the vessel lumen and leading to serious complications, such as stroke and heart attack.
  • Axon - The fiber-like projection or tendril on neurons which conduct messaging away from the cell body to target cells.
  • Missense Mutation - A point-mutation in DNA where one nucleotide in a gene sequence codon has been replaced with a different nucleotide resulting in a different amino acid in the translated protein.
  • Membrane Potential - The difference between chemical concentrations and voltage inside and outside a cell or membrane leading to storage of energy and excitability.
  • Neuropathy - Loss or reduced function of neurons resulting in impaired sensory and/or moter capacity of the nervous system.
  • Respiratory Chain - The process in the inner-mitochondrial membrane whereby high-energy electrons are lost from NADH and FADH2 and pumped into the inter-membrane space and used to drive ATP synthesis.
  • Type 2 Diabetes Mellitus - A disease characterised by hyperglycemia which leads to pancreatic beta-cell exhaustion. Factors contributing include primary beta-cell defects (genetic) and peripheral tissue insulin resistance (as a result of obesity).

References

  1. Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism. A novel regulatory mechanism altered in obesity. Bach D, Pich S, Soriano FX, Vega N, Baumgartner B, Oriola J, Daugaard JR, Lloberas J, Camps M, Zierath JR, Rabasa-Lhoret R, Wallberg-Henriksson H, Laville M, Palacín M, Vidal H, Rivera F, Brand M, Zorzano A. J Biol Chem. 2003 May 9;278(19):17190-7. Epub 2003 Feb 21. PMID: 12598526
  2. Mitofusin 2: a mitochondria-shaping protein with signaling roles beyond fusion.[REVIEW] de Brito OM, Scorrano L. Antioxid Redox Signal. 2008 Mar;10(3):621-33. PMID: 18092941.
  3. OMIM - MITOFUSIN 2; MFN2
  4. OMIM - MITOFUSIN 2; MFN2
  5. Mitofusin 2: a mitochondria-shaping protein with signaling roles beyond fusion.[REVIEW] de Brito OM, Scorrano L. Antioxid Redox Signal. 2008 Mar;10(3):621-33. PMID: 18092941.
  6. Mitofusin-2 regulates mitochondrial and endoplasmic reticulum morphology and tethering: The role of Ras. de Brito OM, Scorrano L. Mitochondrion. 2009 Jun;9(3):222-6. Epub 2009 Mar 6. PMID: 19269351
  7. Mitofusin-2 regulates mitochondrial and endoplasmic reticulum morphology and tethering: The role of Ras. de Brito OM, Scorrano L. Mitochondrion. 2009 Jun;9(3):222-6. Epub 2009 Mar 6. PMID: 19269351
  8. Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism. A novel regulatory mechanism altered in obesity. Bach D, Pich S, Soriano FX, Vega N, Baumgartner B, Oriola J, Daugaard JR, Lloberas J, Camps M, Zierath JR, Rabasa-Lhoret R, Wallberg-Henriksson H, Laville M, Palacín M, Vidal H, Rivera F, Brand M, Zorzano A. J Biol Chem. 2003 May 9;278(19):17190-7. Epub 2003 Feb 21. PMID: 12598526
  9. Mitofusin 2: a mitochondria-shaping protein with signaling roles beyond fusion.[REVIEW] de Brito OM, Scorrano L. Antioxid Redox Signal. 2008 Mar;10(3):621-33. PMID: 18092941.
  10. OMIM - MITOFUSIN 2; MFN2
  11. Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism. A novel regulatory mechanism altered in obesity. Bach D, Pich S, Soriano FX, Vega N, Baumgartner B, Oriola J, Daugaard JR, Lloberas J, Camps M, Zierath JR, Rabasa-Lhoret R, Wallberg-Henriksson H, Laville M, Palacín M, Vidal H, Rivera F, Brand M, Zorzano A. J Biol Chem. 2003 May 9;278(19):17190-7. Epub 2003 Feb 21. PMID: 12598526
  12. Mitofusin 2: a mitochondria-shaping protein with signaling roles beyond fusion.[REVIEW] de Brito OM, Scorrano L. Antioxid Redox Signal. 2008 Mar;10(3):621-33. PMID: 18092941.
  13. Mitofusin 2 protects cerebellar granule neurons against injury-induced cell death. Jahani-Asl A, Cheung EC, Neuspiel M, MacLaurin JG, Fortin A, Park DS, McBride HM, Slack RS, J Biol Chem. 2007 Aug 17;282(33):23788-98. Epub 2007 May 30. PMID: 17537722
  14. Mitofusin-2 regulates mitochondrial and endoplasmic reticulum morphology and tethering: The role of Ras. de Brito OM, Scorrano L. Mitochondrion. 2009 Jun;9(3):222-6. Epub 2009 Mar 6. PMID: 19269351
  15. Mitofusin 2 tethers endoplasmic reticulum to mitochondria. de Brito OM, Scorrano L. Nature. 2008 Dec 4;456(7222):605-10. PMID: 19052620
  16. Mitofusin 2: a mitochondria-shaping protein with signaling roles beyond fusion.[REVIEW] de Brito OM, Scorrano L. Antioxid Redox Signal. 2008 Mar;10(3):621-33. PMID: 18092941.
  17. Mitofusin 2: a mitochondria-shaping protein with signaling roles beyond fusion.[REVIEW] de Brito OM, Scorrano L. Antioxid Redox Signal. 2008 Mar;10(3):621-33. PMID: 18092941.
  18. Mitofusin-2 regulates mitochondrial and endoplasmic reticulum morphology and tethering: The role of Ras. de Brito OM, Scorrano L. Mitochondrion. 2009 Jun;9(3):222-6. Epub 2009 Mar 6. PMID: 19269351
  19. Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism. A novel regulatory mechanism altered in obesity. Bach D, Pich S, Soriano FX, Vega N, Baumgartner B, Oriola J, Daugaard JR, Lloberas J, Camps M, Zierath JR, Rabasa-Lhoret R, Wallberg-Henriksson H, Laville M, Palacín M, Vidal H, Rivera F, Brand M, Zorzano A. J Biol Chem. 2003 May 9;278(19):17190-7. Epub 2003 Feb 21. PMID: 12598526
  20. Mitofusin 2: a mitochondria-shaping protein with signaling roles beyond fusion.[REVIEW] de Brito OM, Scorrano L. Antioxid Redox Signal. 2008 Mar;10(3):621-33. PMID: 18092941.
  21. OMIM - MITOFUSIN 2; MFN2