Mitochondrial fusion

Mitochondrial fusion

Mitochondrial fusion is a process mediated by several large

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References

See also

Mitochondrial fusion plays an important role in the process of embroygenesis, as shown through the Mfn1 and Mfn2 proteins. Using Mfn1 and Mfn2 knock-out mice, which die in utero at midgestation due to a placental deficiency, mitochondrial fusion was shown not to be essential for cell survival in vitro, but necessary for embryonic development and cell survival throughout later stages of development. Mfn1 Mfn2 double knock-out mice, which die even earlier in development, were distinguished from the "single" knockout mice. Mouse embryo fibroblasts (MEFs) originated from the double knock-out mice, which do survive in culture even though there is a complete absence of fusion, but parts of their mitochondria show a reduced mitochondrial DNA (mtDNA) copy number and lose membrane potential. This series of events causes problems with adenosine triphosphate (ATP) synthesis.

The Mfn protein has three different methods of action: Mfn1 homotypic oligomers, Mfn2 homotypic oligomers and Mfn1-Mfn2 heterotypic oligomers. It has been suggested that the type of cell determines the method of action but it has yet to be concluded whether or not Mfn1 and Mfn2 perform the same function in the process or if they are separate. Cells lacking this protein are subject to severe cellular defects such as poor cell growth, heterogeneity of mitochondrial membrane potential and decreased cellular respiration.[6]

Both proteins, Mfn1 and Mfn2, can act either together or separately during mitochondrial fusion. Mfn1 and Mfn2 are 81% similar to each other and about 51% similar to the Drosophila protein Fzo. Results published for a study to determine the impact of fusion on mitochondrial structure revealed that Mfn-deficient cells demonstrated either elongated cells (majority) or small, spherical cells upon observation.

Mitochondrial fusion in mammals

The balance between mitochondrial fusion and fission in cells is dictated by the up-and-down regulation of mitofusins, OPA1/Mgm1, and Drp1/Dnm1. Apoptosis, or programmed cell death, begins with the breakdown of mitochondria into smaller pieces. This process results from up-regulation of Drp1/Dnm1 and down-regulation of mitofusins. Later in the apoptosis cycle, an alteration of OPA1/Mgm1 activity within the inner mitochondrial membrane occurs. The role of the OPA1 protein is to protect cells against apoptosis by inhibiting the release of cytochrome c. Once this protein is altered, there is a change in the cristae structure, release of cytochrome c, and the activation of the destructive caspase enzymes. These resulting changes indicate that inner mitochondrial membrane structure is linked with regulatory pathways in influencing cell life and death. OPA1 plays both a genetic and molecular role in mitochondrial fusion and in cristae remodeling during apoptosis.[4] OPA1 exists in two forms; the first being soluble and found in the intermembrane space, and the second as an integral inner membrane form, work together to restructure and shape the cristae during and after apoptosis. OPA1 blocks intramitochondrial cytochrome c redistribution which proceeds remodeling of the cristae. OPA1 functions to protect cells with mitochondrial dysfunction due to Mfn deficiencies, doubly for those lacking Mfn1 and Mfn2, but it plays a greater role in cells with only Mfn1 deficiencies as opposed to Mfn2 deficiencies. Therefore, it is supported that OPA1 function is dependent on the amount of Mfn1 present in the cell to promote mitochondrial elongation.[5]

Mitochondrial fusion and apoptosis

Many gene products have been identified in controlling mitochondrial fusion. These gene products can be reduced to three core groups, which also control mitochondrial fission. These groups of proteins include mitofusins, OPA1/Mgm1, and Drp1/Dnm1. All of these molecules are GTP hydrolyzing proteins (GTPases) that belong to the dynamin family. Mitochondrial dynamics in different cells are understood by the way in which these proteins regulate and bind to each other.[1] These GTPases in control of mitochondrial fusion are well conserved between mammals, flies, and yeast. Mitochondrial fusion mediators differ between the outer and inner membranes of the mitochondrial. Specific membrane-anchored dynamin family members mediate fusion between mitochondrial outer membranes known as Mfn1 and Mfn2. These two proteins are mitofusin contained within humans that can alter the morphology of affected mitochondria in over-expressed conditions. However, a single dynamin family member known as OPA1 in mammals mediates fusion between mitochondrial inner membranes. These regulating proteins of mitochondrial fusion are organism-dependent; therefore, in Drosophila (fruit flies) and yeasts, the process is controlled by the mitochondrial transmembrane GTPase, Fzo. In Drosophila, Fzo is found in postmeiotic spermatids and the dysfunction of this protein results in male sterility. However, a deletion of Fzo1 in budding yeast results in smaller, spherical mitochondria due to the lack of mitochondrial DNA (mtDNA).

Regulation of mitochondrial fusion

The significance of mitochondrial fission and fusion is distinct for nonproliferating neurons, which are unable to survive without mitochondrial fission. Such nonproliferating neurons cause two human diseases known as dominant optic atrophy and Charcot Marie Tooth disease type 2A, which are both caused by fusion defects. Though the importance of these processes is evident, it is still unclear why mitochondrial fission and fusion are necessary for nonproliferating cells.

[3] The combined effects of continuous fusion and fission give rise to mitochondrial networks. The mechanism of mitochondrial fusion and fission are regulated by

Mitochondrial fusion and fission working together

[1] When cells experience metabolic or environmental

Mitochondrial fusion process overview

Contents

  • Mitochondrial fusion process overview 1
  • Mitochondrial fusion and fission working together 2
  • Regulation of mitochondrial fusion 3
  • Mitochondrial fusion and apoptosis 4
  • Mitochondrial fusion in mammals 5
  • See also 6
  • References 7
Mitochondrial network (green) in two human cells (HeLa cells)
Mitochondria, mammalian lung - TEM (2)

The process of mitochondrial fusion incorporates a variety of proteins, which assist the cell throughout the series of events that form this specific process. [1]