Its main functions include: (i) increasing mitochondrial numbers to ensure mitochondria are passed on to daughter cells during mitosis (Taguchi et al., 2007) (ii) enabling shuttling of mitochondria to other regions of the cell (iii) signalling to the cell that it is damaged and needs to be removed by mitophagy thereby maintaining a healthy mitochondrial network (Lee et al., 2011) and (iv) the initiation of apoptotic cell death (Lee et al., 2004). Mitochondrial fission describes the fragmentation or division of one mitochondrion into two or more mitochondria. How a deficiency in the mitochondrial fusion protein MFN2 or OPA1 results in such a specific neurological condition is currently unknown. Mutations in the OPA1 gene were first identified in 2000 and found to be associated with the human neurogenerative condition, autosomal dominant optic atrophy (Delettre et al., 2000). Mutations in human MFN2 are responsible for the autosomal dominant neurodegenerative disease Charcot-Marie-Tooth type 2A, a peripheral sensorimotor neuropathy (Zuchner et al., 2004). Whole body genetic ablation of MFN1 and MFN2 results in embryonic lethality due to a major placental defect (Chen et al., 2003). This lack of IMM fusion and matrix content mixing result in loss of mitochondrial heterogeneity and the occurrence of metabolic disturbances, confirming that a key role of mitochondrial fusion is the mixing of matrix contents (mitochondrial DNA, metabolites and proteins) (Chen et al., 2005 Song et al., 2009). In the absence of OPA1, MFN1 and MFN2 mediate only superficial mitochondrial fusion with the IMMs remaining unfused. Fusion of IMM is mediated by OPA1 (Malka et al., 2005 Song et al., 2009), which itself is regulated by nuclease cleavage at the mRNA level, and proteolytic cleavage at the protein level (Song et al., 2007). MFN1 and MFN2 mediate OMM fusion through the formation of either heterodimers or homodimers (MFN2 binding to MFN2) (Chen et al., 2003 Koshiba et al., 2004). These proteins hydrolyze GTP to fuse two neighbouring mitochondria together to allow sharing of mitochondrial DNA, proteins and metabolites. The fusion proteins are the outer mitochondrial membrane (OMM) proteins, mitofusin 1 (MFN1) and mitofusin 2 (MFN2), and the inner mitochondrial membrane (IMM) protein, optic atrophy factor 1 (OPA1) (as shown in Figure 1). This review investigates the role of the mitochondrial fusion and fission proteins as novel therapeutic targets for combating cardiovascular disease. In particular, the field of mitochondrial dynamics, in which mitochondria are dynamic organelles, and are able to change their morphology by undergoing fusion and fission, has recently been investigated and shown to be relevant to the cardiovascular system (Ong et al., 2013). These important secondary roles mean that mitochondrial biology is a rejuvenated field, with mitochondrial dysfunction at the root of numerous diseases. While their primary role is to generate ATP, mitochondria also play a number of important roles which affect cell survival and death (Pellegrini and Scorrano, 2007). This is especially true in the heart, where the mitochondria occupy around 30% of the total cell volume and produce a staggering 30 kg of ATP per day, in order to sustain normal contractile function of the heart. Mitochondria are essential for eukaryotic life, meeting the cells’ energetic requirements through oxidative phosphorylation.

Fusion and fission of mitochondria