Loss of mitochondrial function is important in aging. Mitochondria are the power plants of the cell, a herd of bacteria-like organelles that contain their own mitochondrial DNA, constantly replicate by division or fuse together, and work to package the chemical energy store molecule adenosine triphosphate, used to power cellular processes. Numerous mechanisms are implicated in the age-related disruption of mitochondrial function, and many of them relate to quality control, either of individual mitochondrial proteins, or of the entire mitochondrion. For example, there is evidence for an age-related imbalance in mitochondrial fusion and fission to lead to overly large mitochondria that are resistant to the quality control mechanism of mitophagy – and thus they become worn and dysfunctional and are not replaced.
Pathophysiological stress often damages mitochondria in myocytes which are vital for the heart’s contractile activity. Therefore, continuous monitoring and repair of mitochondria are needed to maintain a healthy mitochondrial population in cells. Multiple levels of mitochondrial quality control exist both at the protein and organelle level.
First, because the majority of mitochondrial proteins are encoded in the nucleus, significant monitoring of mitochondrial precursor proteins is needed during their cytosolic translation and import. The ubiquitin-proteasome system shapes the mitochondrial proteome through steady-state turnover of mitochondrial precursors to ensure an appropriate stoichiometry between nuclear and mitochondrially encoded proteins and their proper localization. Second, mitochondria contain resident chaperones and proteases to ensure quality control within the mitochondria. Third, excessive levels of misfolded proteins in the mitochondrial matrix or a mito-nuclear protein imbalance activates a conserved mitochondrial ubuqiutin-proteasome system which functions to selectively induce a transcriptional response aimed at restoring mitochondrial proteostasis.
A closer examination into these processes reveals an inextricable link between mitochondrial quality control and cytosolic proteostasis. More recently, mitochondria themselves have been found to participate in general protein quality control through the import and degradation of misfolded cytosolic proteins.
In the event that the mitochondria cannot be repaired, myocytes have the option of either eliminating damaged mitochondrial components via mitochondrial-derived vesicles, or by removing the entire organelle through mitophagy. Elimination of the entire mitochondria is likely a last resort response because it requires the cell to replace the mitochondrion.
Continued investigations into the molecular drivers of mitochondrial quality have the potential to elucidate novel interventions for general the proteostatic stress seen during myocardial ischemia, pressure overload, and protein aggregation cardiomyopathies. Collectively, these mitochondrial quality control pathways represent essential adaptive responses in cardiac myocytes, and fruitful avenues for the development of novel therapies against cardiovascular diseases. Once a better understanding of the regulators and relationships between the various quality control pathways is gained, we will hopefully be able to translate this knowledge into improved treatments for disease.