Mitochondrial fusion and fission proteins: novel therapeutic targets for combating cardiovascular disease

Abstract

Mitochondria are no longer considered to be solely the static powerhouses of the cell. While they are undoubtedly essential to sustaining life and meeting the energy requirements of the cell through oxidative phosphorylation, they are now regarded as highly dynamic organelles with multiple functions, playing key roles in cell survival and death. In this review, we discuss the emerging role of mitochondrial fusion and fission proteins, as novel therapeutic targets for treating a wide range of cardiovascular diseases.

Keywords: Drp1; MFN1; MFN2; OPA1; mitochondrial dynamics; mitochondrial fission; mitochondrial fusion; mitochondrial morphology.

Figure 1

Mitochondrial fusion and fission proteins and their roles in changing mitochondrial morphology. MFN1, MFN2 and OPA1 are all key to mediating mitochondrial fusion, while Drp1 interacts with Fis1, MFF and MiD49/51 to mediate mitochondrial fission. Secondary to these mitochondrial-shaping roles, MFN2 tethers the SR/ER to the mitochondria allowing efficient Ca²⁺ transfer between the organelles. The mitochondria are also key to apoptosis with BAK and BAX binding to MFN2 stabilizing Drp1 binding. Drp1 binding leads to mitochondrial fragmentation and the release of cytochrome c. Cytochrome c is normally sequestered by OPA1 in the cristae, although the OPA1 oligomers maintaining cristae shape are disrupted by BAK and BAX binding.

Figure 2

This scheme depicts the mitochondrial fission and fusion proteins as novel therapeutic targets for treating cardiovascular disease. It is important to bear in mind that chronic therapeutic targeting of these shaping proteins may have detrimental effects and that there may be off-target effects as these mitochondrial-shaping proteins may have non-fusion or non-fission pleiotropic actions within the cell.