The Role of AAA+ Proteases in Mitochondrial Protein Biogenesis, Homeostasis and Activity Control

Abstract

Mitochondria are specialised organelles that are structurally and functionally integrated into cells in the vast majority of eukaryotes. They are the site of numerous enzymatic reactions, some of which are essential for life. The double lipid membrane of the mitochondrion, that spatially defines the organelle and is necessary for some functions, also creates a physical but semi-permeable barrier to the rest of the cell. Thus to ensure the biogenesis, regulation and maintenance of a functional population of proteins, an autonomous protein handling network within mitochondria is required. This includes resident mitochondrial protein translocation machinery, processing peptidases, molecular chaperones and proteases. This review highlights the contribution of proteases of the AAA+ superfamily to protein quality and activity control within the mitochondrion. Here they are responsible for the degradation of unfolded, unassembled and oxidatively damaged proteins as well as the activity control of some enzymes. Since most knowledge about these proteases has been gained from studies in the eukaryotic microorganism Saccharomyces cerevisiae, much of the discussion here centres on their role in this organism. However, reference is made to mitochondrial AAA+ proteases in other organisms, particularly in cases where they play a unique role such as the mitochondrial unfolded protein response. As these proteases influence mitochondrial function in both health and disease in humans, an understanding of their regulation and diverse activities is necessary.

Mitochondrial matrix proteostasis is linked to hereditary paraganglioma: LON‐mediated turnover of the human flavinylation factor SDH5 is regulated by its interaction with SDHA

“…Interestingly, these data identified 2 N‐terminal sequences; the predominant N‐terminal sequence, YRGDS, was consistent with processing ( Fig. 3 A ,I ) by the mitochondrial processing peptidase (MPP) at an R‐2 recognition motif (9, 10, 32, 33), while the second N‐terminal sequence, GDSxT (where x was unknown), although minor, was consistent with a second processing step that generates the mature protein (Fig. 3 A , II) similar to that observed for yeast Sdh5 (EMI5) (33).…”

“…Nuclear‐encoded mitochondrial matrix proteins synthesized with an N‐terminal mitochondrial targeting signal, such as SDH5, follow the presequence pathway of import into the organelle (8). Following import and processing, the mature protein is subject to protein maintenance by the resident mitochondrial protein quality control (PQC) network, which consists of molecular chaperones and proteases (9, 10). Human mitochondria have 4 distinct ATPases associated with various cellular activities (AAA + ) proteases: the inner membrane‐anchored intermembrane space and matrix active AAA proteases and the matrix proteases mitochondrial Lon (LONM) and casein lytic protease XP (CLPXP) (10, 11).…”

“…Following import and processing, the mature protein is subject to protein maintenance by the resident mitochondrial protein quality control (PQC) network, which consists of molecular chaperones and proteases (9, 10). Human mitochondria have 4 distinct ATPases associated with various cellular activities (AAA + ) proteases: the inner membrane‐anchored intermembrane space and matrix active AAA proteases and the matrix proteases mitochondrial Lon (LONM) and casein lytic protease XP (CLPXP) (10, 11). CLPXP is a barrel‐shaped protease composed of 2 oligomeric complexes, a hexameric AAA + protein (CLPX) and a peptidase (CLPP), which consists of 2 heptameric rings stacked back to back (12).…”

Mitochondrial protein quality control in health and disease

“…Protein quality control in the mitochondrial inner membrane is primarily monitored by two AAA proteolytic complexes, the i-AAA protease and m-AAA protease, which are oriented with their respective active sites facing the intermembrane space (i-AAA) or matrix (m-AAA) ( Figure 2) (Leonhard et al, 1996;Tatsuta and Langer, 2009;Voos et al, 2013). The i-AAA protease is a homo-oligomeric machine composed of a single protein subunit known as Yme1 (yeast mitochondrial escape protein 1) in both yeast and humans (known as YME1L).…”

Molecular Identification of Cysteine and Trypsin Protease, Effect of Different Hosts on Protease Expression, and Rnai Mediated Silencing of Cysteine Protease Gene in the Sunn Pest

“…Protein‐digesting enzymes play important roles in many biological processes including cell proliferation (Lee et al., ), morphogenesis and tissue remodeling (Reichhart et al., ), homeostasis (Voos et al., ), wound healing (Karlsson et al., ), immunity (Gorman et al., ; Manoury et al., ), apoptosis (Zhang and Li, ), and food digestion (Saadati and Bandani, ). Insects use salivary glands and gut digestive proteases to degrade diet proteins to peptides and to amino acids (Sato et al., ; Dunse et al., 2010a,b).…”