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Mitochondrial Fusion
Mitochondrial fusion and fission function to maintain the architectural structure of these membrane-bound organelles, as well as allowing for cooperation between mitochondria, protecting them from respiratory dysfunction. Without the balance of these interconnected processes, and increased activity of fusion leads to mitochondrial elongation whereas increased fission results in mitochondrial fragmentation. The components of this process can influence programmed cell death and lead to neurodegenerative disorders. The proteins which regulate this process 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). In humans, the proteins that regulate mitochondrial fusion are mitofusin, Mfn1 and Mfn2, which can alter the morphology of affected mitochondria in over-expressed conditions.

Mitochondrial Fusion and Programmed Cell Death

When mitochondrial fission is overactive, it leads to mitochondrial fragmentation, dependent on the dynamin-related protein (Drp1) 1. This fragmentation initiates a signaling cascade for the pathway of programmed cell death. Optic Atrophy 1 (OPA1) is a profusion Drp1 found on the inner mitochondrial membrane and acts independently from the mitochondrial fusion process. This protein is shown protect cells against apoptosis by inhibiting cytochrome C release. When this enzyme is released, it fragments the organelle and remodels the cristae of the mitochondria. Therefore, OPA1 functions to control the shape of the cristae, keeping the junctions tight during apoptosis. 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 does not interfere with BAX or BAK, which belong to the BCL-2 family and participate in the regulation of mitochondrial gates which release cytochrome C. Instead, active 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.

Mitochondrial Fusion in Mammals

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.

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.

References