Comprehensive Analysis of Mitochondrial Dynamics Alterations in Heart Diseases

Figure 1. Fusion/Fission machinery. Schematic representation of mitochondrial fusion and fission machinery and their crosstalk with biogenesis. (a) Mitochondrial players involved in fusion, fission and biogenesis. (b) Mitochondrial fission is orchestrated by a series of molecular events involving OMM receptors (MFF, MiD49, MiD51, FIS1), which help the recruitment of DRP1 to the organelle. DRP1 results to be the main protein effector of mitochondrial fragmentation. (c) Mitochondrial fusion is allowed by the tethering properties of MFNs and the function of OPA1 at the IMM. (d) Mitochondrial biogenesis is at the crosstalk of a nuclear/mitochondrial gene reprogramming involving the upregulation of PGC-1α, NRF1/2, TFAM, their nuclear interactions and fusion proteins.

Figure 2. Mitochondrial dynamics alterations in heart diseases. Schematic overview of molecular pathways through which mitochondrial fission, fusion and biogenesis contribute to pathological aspects of heart diseases. Overall, mitochondrial fragmentation is the main common feature of heart diseases reported in this review. The ways by which mitochondria become fragmented are multiple and are aimed to anchor DRP1 to mitochondria. In CAD, a link with the HIF-1α has been found and involves the downregulation of miR-138; a second miRNA, miR-19b, blocks SOCS6 kinase function to prevent DRP1 phosphorylation on Ser-637. The same effect is obtained by the increase in activity of calcineurin. A concomitant decrease in mitochondrial fusion has been reported: in atherosclerosis development, apelin-13 promotes the downregulation of MFNs and OPA1. Also, mitochondrial biogenesis is downregulated through the loss of PGC-1α, NRF1/2 and TFAM expression, especially in CAD and in rhythm disorders in a Hippo pathway-dependent manner. Red arrows: downregulation of a given protein/pathway; blue arrows: upregulation of a given protein/pathway; black arrows: cause-effect link.