Abstract
Mitochondria perform numerous functions necessary for the survival of eukaryotic cells. These activities are coordinated by a diverse complement of proteins encoded in both the nuclear and mitochondrial genomes that must be properly organized and maintained. Misregulation of mitochondrial proteostasis impairs organellar function and can result in the development of severe human diseases. ATP-driven AAA+ proteins play crucial roles in preserving mitochondrial activity by removing and remodeling protein molecules in accordance with the needs of the cell. Two mitochondrial AAA proteases, i-AAA and m-AAA, are anchored to either face of the mitochondrial inner membrane, where they engage and process an array of substrates to impact protein biogenesis, quality control, and the regulation of key metabolic pathways. The functionality of these proteases is extended through multiple substrate-dependent modes of action, including complete degradation, partial processing, or dislocation from the membrane without proteolysis. This review discusses recent advances made toward elucidating the mechanisms of substrate recognition, handling, and degradation that allow these versatile proteases to control diverse activities in this multifunctional organelle.
Highlights
Mitochondria provide eukaryotic cells with a stage for performing essential activities, including mass ATP production, calcium ion storage, and fatty acid oxidation (Chan, 2006; McBride et al, 2006)
A recent report has suggested that the proteolytic capacity of mitochondria is used to clear cytosolic protein aggregates that are associated with aging (Ruan et al, 2017)
Significant progress has been made in recent years in expanding the repertoire of functions performed by the mitochondrial AAA proteases and understanding how these enzymes select and process substrates
Summary
Mitochondria provide eukaryotic cells with a stage for performing essential activities, including mass ATP production, calcium ion storage, and fatty acid oxidation (Chan, 2006; McBride et al, 2006). Homology modeling using crystal structures of FtsH reveals these mutations largely cluster to positions surrounding the metalloprotease active site and subunit interfaces (Figure 2B) and are likely to cause defects in polypeptide cleavage and hexamer assembly rather than substrate binding or ATP hydrolysis.
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