Abstract
Mitochondria are the key to properly functioning energy generation in the metabolically demanding cardiomyocytes and thus essential to healthy heart contractility on a beat-to-beat basis. Mitochondria being the central organelle for cellular metabolism and signaling in the heart, its dysfunction leads to cardiovascular disease. The healthy mitochondrial functioning critical to maintaining cardiomyocyte viability and contractility is accomplished by adaptive changes in the dynamics, biogenesis, and degradation of the mitochondria to ensure cellular proteostasis. Recent compelling evidence suggests that the classical protein quality control system in cardiomyocytes is also under constant mitochondrial control, either directly or indirectly. Impairment of cytosolic protein quality control may affect the position of the mitochondria in relation to other organelles, as well as mitochondrial morphology and function, and could also activate mitochondrial proteostasis. Despite a growing interest in the mitochondrial quality control system, very little information is available about the molecular function of mitochondria in cardiac proteostasis. In this review, we bring together current understanding of the adaptations and role of the mitochondria in cardiac proteostasis and describe the adaptive/maladaptive changes observed in the mitochondrial network required to maintain proteomic integrity. We also highlight the key mitochondrial signaling pathways activated in response to proteotoxic stress as a cellular mechanism to protect the heart from proteotoxicity. A deeper understanding of the molecular mechanisms of mitochondrial adaptations and their role in cardiac proteostasis will help to develop future therapeutics to protect the heart from cardiovascular diseases.
Highlights
Proteins are complex macromolecules with versatile molecular functions implicated in every biological process (Hartl et al, 2011)
The term “proteotoxicity” refers to the cellular pathogenic features that result from protein misfolding and aggregation, which is regulated by myriad factors that affect protein folding and misfolding
We recently reported that the D7-Des Tg mouse model of desmin-related cardiomyopathy (DRC) demonstrated altered mitochondrial morphology and localization along the sarcomere resulting in mitochondrial dysfunction (Alam et al, 2018)
Summary
Proteins are complex macromolecules with versatile molecular functions implicated in every biological process (Hartl et al, 2011). If refolding is impossible due to the extent of misfolding and/or the size of the protein, the ubiquitin-proteosome system or autophagy (including mitochondrial autophagy, mitophagy) ensures protein degradation as a secondary defense mechanism. Some pathological conditions result in the PQC system becoming so overwhelmed that misfolded proteins accumulate, resulting in aggregate formation (Fauconnier, 2018). In addition to these classical PQC system processes, mitochondria play an important role in cytosolic proteostasis through the uptake of aggregates by the mitochondrial import system, which degrades them using mitochondrial serine proteases (Ruan et al, 2017). This review encompasses current understanding of the molecular insights concerning the adaptive changes in mitochondria in cardiac proteostasis, the maladaptive effect of mitochondrial dysfunction in cardiac proteostasis, and the impact of impaired cardiac proteostasis on mitochondrial function
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