Mitochondria Fusion and Fission

Abstract

Mitochondrial structural dynamics is regulated by the fusion or fission of these organelles. Recently published evidence indicates the vital role of mitochondrial fusion and fission in cellular physiology, including progression of apoptosis. These reports indicate that in addition to intimate link between mitochondrial morphogenesis machineries and regulation of mitochondrial steps in apoptosis, certain proteins vital for the regulation of mitochondrial steps in apoptosis can also regulate mitochondrial fusion and fission in healthy cells. In this article, we focus on the regulation of mitochondrial network dynamics. The emerging evidence indicating that proteins implicated in mitochondrial network dynamics are vital for the mitochondrial steps in apoptosis is presented here, as well. Furthermore, the data demonstrating an unexpected role for the B‐cell lymphoma (Bcl)‐2 family members in the regulation of mitochondrial morphogenesis are also discussed.

Key concepts:

  • In healthy cells, mitochondrial cycle between several shapes, their morphology result from the equilibrium between mitochondrial fusion and fission.

  • The unique feature of mitochondrial fusion is the necessity of merging double membrane systems from the two fusing mitochondria. This process is mediated by the outer mitochondrial membrane‐associated mitofusin proteins (Mfn1 and Mfn2), and the inner mitochondrial membrane‐associated Opa1.

  • Regulation of mitochondrial fusion and fission has a significant impact on cell viability and early development.

  • The mitochondrial fragmentation occurs concomitantly with the outer mitochondrial membrane (OMM) permeabilization, a critical step in apoptosis.

  • The cooperation between proteins involved in mitochondrial fusion and fission and Bcl‐2 family proteins during apoptosis suggests that changes in mitochondrial network dynamics contribute to apoptotic signalling.

  • The mechanistic link between the core mitochondrial fusion and fission regulating proteins (e.g. Drp1, Mfn2 and Opa1) and proteins from Bcl‐2 family, suggest that Bcl‐2 family proteins also regulate mitochondrial dynamics in healthy cells.

Keywords: mitochondria; fusion; fission; apoptosis; GTPase; Bcl‐2

Figure 1.

Visualization of mitochondrial remodelling and fusion using mito‐PAGFP. The region of interest (ROI) in a mito‐PAGFP (Karbowski et al., ) transfected mouse embryonic fibroblast was photoactivated with 413‐nm light followed by time‐lapse acquisition of images using 488‐nm laser excitation. Note that between 1 and 2 min the redistribution of mito‐PAGFP from activated to nonactivated mitochondria occurs, indicating mitochondrial fusion.

Figure 2.

Mitochondrial fusion and fission regulate cellular organization of these organelles. The mitochondrial architecture oscillates between long tubules and small round vesicles (control), resulting in a dynamic organizational equilibrium. This equilibrium is achieved through the continuously occurring but opposing processes of mitochondrial fusion and fission. The relative contribution of each process determines the overall degree of continuity, branching and the average size of mitochondria within the cell. The effects of Drp1K38A and vMIA on mitochondrial morphology, which when overexpressed inhibits mitochondrial fission or fusion, respectively, exemplify this feature. Note highly elongated and interconnected mitochondria in Drp1K38A expressing cells and short, vesicular mitochondria induced by expression of vMIA. Cos‐7 cells transfected with mito‐YFP alone, or together with Drp1K38A or vMIA are shown.

Figure 3.

Regulation of mitochondrial morphology by fusion and fission. An overview of proteins vital for mitochondrial fusion and fission. The multimeric dynamin‐like GTPaseDrp1 is a critical protein mediating mitochondrial fission. Under normal growth conditions a major cellular fraction of Drp1 localizes to the cytosol, and the translocation of Drp1 to the OMM is needed to initiate mitochondrial fission. The OMM‐associated pool of Drp1 form punctate foci that often colocalize with the progressive mitochondrial fission sites. Mitochondrial fusion is mediated by two large GTPases in the OMM, mitofusins (Mfn) 1 and 2, and by optic atrophy 1 (Opa1), a dynamin related protein in the IMM.

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Further Reading

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Benard, Giovanni, Peng, Guihong, and Karbowski, Mariusz(Sep 2009) Mitochondria Fusion and Fission. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021577]