Mitochondrial Quality Control and Cellular Proteostasis: Two Sides of the Same Coin

Abstract

Mitochondrial dysfunction is a hallmark of cardiac pathophysiology. Defects in mitochondrial performance disrupt contractile function, overwhelm myocytes with reactive oxygen species (ROS), and transform these cellular powerhouses into prodeath organelles. Thus, quality control (QC) pathways aimed at identifying and removing damaged mitochondrial proteins, components, or entire mitochondria are crucial processes in post-mitotic cells such as cardiac myocytes. Almost all of the mitochondrial proteins are encoded by the nuclear genome and the trafficking of these nuclearencoded proteins necessitates significant cross-talk with the cytosolic protein QC machinery to ensure that only functional proteins are delivered to the mitochondria. Within the organelle, mitochondria contain their own protein QC system consisting of chaperones and proteases. This system represents another level of QC to promote mitochondrial protein folding and prevent aggregation. If this system is overwhelmed, a conserved transcriptional response known as the mitochondrial unfolded protein response is activated to increase the expression of proteins involved in restoring mitochondrial proteostasis. If the mitochondrion is beyond repair, the entire organelle must be removed before it becomes cytotoxic and causes cellular damage. Recent evidence has also uncovered mitochondria as participants in cytosolic protein QC where misfolded cytosolic proteins can be imported and degraded inside mitochondria. However, this process also places increased pressure on mitochondrial QC pathways to ensure that the imported proteins do not cause mitochondrial dysfunction. This review is focused on discussing the pathways involved in regulating mitochondrial QC and their relationship to cellular proteostasis and mitochondrial health in the heart.

The proteasome: friend and foe of mitochondrial biogenesis

“…The central relevance of the proteasome for aging cells is not limited to neurons, but also well established for the skeletal and cardiac muscle cells of. Owing to their permanent activity, their high energy consumption, and mechanical stress conditions, (cardio)myocytes are indeed particularly vulnerable to proteotoxic stress [13,144,145].…”

“…There is no doubt that the mitochondrial quality control system is crucial to maintain mitochondrial proteostasis and for the dynamic adaptation of the mitochondrial proteome to changing metabolic conditions [9][10][11][12]. Nevertheless, studies over the past decade have shown that the ubiquitin-proteasome system (UPS) of the cytosol is of pivotal relevance for the surveillance of the mitochondrial proteome [13][14][15][16][17]. Particularly important in this context are the degradation of cytosolic mitochondrial precursor proteins and that of mitochondrial surface proteins, the so-called mitochondria-associated degradation (MAD), by the proteasome.…”

LPS-Induced Endotoxemia Evokes Epigenetic Alterations in Mitochondrial DNA That Impacts Inflammatory Response

“…This is in line with our recent study showing that the mitochondrial transcription factor A (TFAM), which is also upregulated after LPS treatment suffers from the same dilemma, namely not reaching the mitochondria [ 17 ]. Taken together, our results hint at an insufficient translocation of mitochondrial proteins that need to be shuttled from the cytoplasm into the mitochondrial matrix [ 18 ]. These results, therefore, underline that when studying mitochondria, the protein abundance within the mitochondria needs to be considered in addition to their cellular expression.…”

The Cellular Stress Response Interactome and Extracellular Matrix Cross-Talk during Fibrosis: A Stressed Extra-Matrix Affair

“…Mitochondria and endoplasmic reticulum (ER) in cardiomyocytes are overrepresented organelles to co-ordinate the increased metabolic demands and maintain active calcium stores for smooth flow. Endoplasmic reticulum and mitochondria quality control circuits are also integral to cardiac function, and deregulation of these pathways are strongly implicated in cardiac diseases including heart failure [57][58][59][60][61][62][63]. ECM remodeling is emerging to coincide with metabolic rewiring in cardiomyocytes and matrixguided control of mitochondrial function in cardiomyocytes is seen as a potential therapeutic target in cardiac fibrosis, repair, regeneration and tissue engineering [64].…”