Mitochondrial fusion and fission: The fine-tune balance for cellular homeostasis

Abstract

Mitochondria are highly dynamic, maternally inherited cytoplasmic organelles, which fulfill cellular energy demand through the oxidative phosphorylation system. Besides, they play an active role in calcium and damage-associated molecular patterns signaling, amino acid, and lipid metabolism, and apoptosis. Thus, the maintenance of mitochondrial integrity and homeostasis is extremely critical, which is achieved through continual fusion and fission. Mitochondrial fusion allows the transfer of gene products between mitochondria for optimal functioning, especially under metabolic and environmental stress. On the other hand, fission is crucial for mitochondrial division and quality control. The imbalance between these two processes is associated with various ailments such as cancer, neurodegenerative and cardiovascular diseases. This review discusses the molecular mechanisms that control mitochondrial fusion and fission and how the disruption of mitochondrial dynamics manifests into various disease conditions.

Keywords: diseases; dynamics; fission; fusion; mitochondria.

Figure 1.

Structure of a mitochondrion showing the outer mitochondrial membrane, inner mitochondrial membrane, intermembrane space and the mitochondrial matrix. Mitochondrial genome residing in the mitochondrial matrix has 37 genes coding for 13 OXPHOS proteins (in red, **), 2 ribosomal RNAs (12s rRNA, 16s rRNA,*), 22 tRNAs (***) and a regulatory D loop region.

Figure 2.

Schematic diagram of the structure of fusion (MFN1, MFN2, OPA1) and fission (DRP1) regulators. MFN1- Mitofusin 1, MFN2- Mitofusin 2, OPA1- Optic atrophy protein 1, DRP1- Dynamin related protein 1, TM- transmembrane, PR- proline rich, HR1- helical repeat 1, HR2- helical repeat 2, N- N terminal, C- C terminal, MTS- mitochondrial targeting sequence, BSE- bundle signaling element.

Figure 3.

The fusion paradigm. Depiction of various steps involved in mitochondrial fusion. (a) GTP binding and hydrolysis leads to a conformational change in the GTPase domains of MFNs resulting in their oligomerization. The oligomerization of the GTPase domains brings about the tethering of the two mitochondria, which facilitates their docking and fusion. (b) A new mechanism of the oligomerization of MFN molecules. Increased oxidized glutathione levels oxidizes two cysteine residues located in the HR2 domains of MFN molecules. This leads to the formation of disulphide bonds between MFN molecules and their oligomerization. MFNs- Mitofusins, OPA1- Optic atrophy protein 1, GTP- Guanosine triphosphate, GDP- Guanosine diphosphate, Pi- inorganic phosphate, HR2- helical repeat 2.

Figure 4.

Mitochondrial fission machinery. The steps involved in mitochondrial fission are as follows- ER tubules contact the mitochondria to mediate constriction before the recruitment of DRP1. After the recruitment of DRP1 to the OMM, it forms a ring like structure, GTP hydrolysis of DRP1 then occurs followed by the recruitment of DNM2 to the mitochondrion-constricted site, where it assembles and completes the division process leading to two daughter mitochondria. ER- Endoplasmic reticulum, DRP1- Dynamin related protein 1, DNM2- Dynamin 2, GTP- Guanosine triphosphate, GDP- Guanosine diphosphate, Pi- inorganic phosphate, OMM- Outer mitochondria membrane.