Disruption of Mitochondrial Dynamics in Cardiovascular Disease
Mitochondria are the power plants of the cell, a herd of replicating bacteria-like organelles that contain their own small genomes. They are responsible for packaging the chemical energy store molecules used to power cell processes. Mitochondria constantly undergo fusion and fission, and otherwise promiscuously pass around their component parts. The population in each cell is gardened by the quality control mechanism of mitophagy that works to remove damaged mitochondria. There is good evidence to suggest that, with aging, changes in gene expression cause a growing imbalance between fission and fusion, leading to large mitochondria that are resistant to mitophagy even when dysfunctional. This occurs in all cells, in comparison to another mechanism by which a comparatively few cells suffer mitochondrial DNA damage that causes them to become very dysfunctional and churn out oxidative molecules that disrupt tissue function throughout the body. Loss of energy production has a major impact in all tissues, but particularly in the energy-hungry tissues of muscle and brain.
Mitochondria are highly dynamic and constantly undergo morphological changes between fission (division) and fusion in response to various metabolic and environmental cues. A fusion process assists to homogenize the contents of damaged mitochondria resulting in mitochondrial elongation. Fission, on the other hand, leads to mitochondrial fragmentation and promotes clearance of damaged mitochondria through a form of selective autophagy - mitophagy. Excessive or untimely fission or fusion may be detrimental to mitochondrial quality and mitochondrial homeostasis.
Defective segments of mitochondria are segregated from the rest of the mitochondrial network through fission for elimination by mitophagy. Fragmented mitochondria and decreased baseline of mitophagy have been noted in aging hearts. Several proteins involved in mitochondrial turnover such as PINK1 and PGC-1α tend to decrease in old animals. These data indicated a decline in the function and regulation of mitophagy during aging. Recent studies suggested that aging-related mitochondrial DNA mutations may disrupt the receptor- (NIX and FUNDC1) mediated mitophagy in the differentiation process in adult cardiac progenitor cells (CPCs), which resulted in sustained fission and less functional fragmented mitochondria. Therefore, some activators of mitophagy have been used in aging models and showed some beneficial effects. For instance, urolithin A has been widely reported to extend lifespan in C. elegans and improve physical exercise capacity in rodents through upregulating mitophagy.
However, why and how mitophagy declines during aging have not been well defined. Several hypotheses were speculated thus far. For example, it was reported S-nitrosoglutathione reductase (GSNOR/ADH5), a protein denitrosylase that regulates S-nitrosylation, was downregulated with aging in mice and humans. Accumulation of S-nitrosylation severely impaired mitophagy, rather than autophagy, leading to hyperactivated mitochondrial fission.
In essence, mitophagy is considered a self-defense and garbage removal process that maintains mitochondrial homeostasis and cellular health, in the face of pathological stimuli. Dozens of species have depicted a unique protective role of mitophagy in aging and cardiovascular diseases, an effect consistent with suppressed mitophagy in multiple pathways. The baseline of mitophagy in different cardiac diseases may help understand the complex effects of mitophagy. The presence of a switch from AMPKα2 to AMPKα1 in failing hearts has been well documented, leading to a decrease of AMPKα2-mediated mitophagy and development of heart failure. In another independent study, upregulated CK2α following acute cardiac ischemia-reperfusion injury was found to suppress FUNDC1-mediated mitophagy, leading to infarct area expansion and cardiac dysfunction. Furthermore, ischemia activated FUNDC1-mediated mitophagy while reperfusion suppressed mitophagy possibly through activating Ripk3. Not surprisingly, interventions that restored mitophagy to normal levels, but not above normal levels, in these conditions should help to maintain mitochondrial homeostasis and cellular function.