Metalloproteases of the Inner Mitochondrial Membrane

Abstract

The inner mitochondrial membrane (IM) is among the most protein-rich cellular compartments. The metastable IM subproteome where the concentration of proteins is approaching oversaturation creates a challenging protein folding environment with a high probability of protein malfunction or aggregation. Failure to maintain protein homeostasis in such a setting can impair the functional integrity of the mitochondria and drive clinical manifestations. The IM is equipped with a series of highly conserved, proteolytic complexes dedicated to the maintenance of normal protein homeostasis within this mitochondrial subcompartment. Particularly important is a group of membrane-anchored metallopeptidases commonly known as m-AAA and i-AAA proteases, and the ATP-independent Oma1 protease. Herein, we will summarize the current biochemical knowledge of these proteolytic machines and discuss recent advances in our understanding of mechanistic aspects of their functioning.

Mitostasis in Neurons: Maintaining Mitochondria in an Extended Cellular Architecture

“…The significance of these proteases for mitochondrial quality control in neurons is clear from the neurologic phenotypes associated with mutations in their genes. These phenotypes include non-syndromic mental retardation, spastic paraplegia, and spastic and spinocerebellar ataxias (Levytskyy et al, 2017). When oxidative damage has occurred, this mode of protein turnover may be considered the mitochondrion’s first line of defense, capable of removing a potentially problematic protein as soon as it forms.…”

Proteolytic ectodomain shedding of membrane proteins in mammals—hardware, concepts, and recent developments

“…Several other proteolytic events in cells, such as removal of a signal peptide by signal peptidase (Blobel & Dobberstein, ) and proteolytic cleavages by mitochondrial AAA proteases (Levytskyy et al , ), formally share similarities to ectodomain shedding, but will not be discussed in this review, as they occur either during protein biosynthesis but not on the mature protein (signal peptidase), or do not occur in the secretory or endocytic pathway (mitochondria).…”

“…Cleavage sites within the juxtamembrane region are typically at a short distance of often 10 -35 amino acids from the TM segment, but more distant cleavage sites are possible and, in fact, the exact cleavage sites have only been determined for few shedding substrates (e.g., summarized for ADAMs and BACE1 in Caescu et al, 2009;Yan, 2017). Several other proteolytic events in cells, such as removal of a signal peptide by signal peptidase (Blobel & Dobberstein, 1975) and proteolytic cleavages by mitochondrial AAA proteases (Levytskyy et al, 2017), formally share similarities to ectodomain shedding, but will not be discussed in this review, as they occur either during protein biosynthesis but not on the mature protein (signal peptidase), or do not occur in the secretory or endocytic pathway (mitochondria).…”

Loss of the mitochondrial i ‐ AAA protease YME 1L leads to ocular dysfunction and spinal axonopathy

“…YME1L preserves mitochondrial proteostasis and function acting both as a quality control and as a regulatory enzyme in the IM (Quiros et al, 2015;Levytskyy et al, 2017). Besides cleaving OPA1, it degrades damaged or non-assembled IM proteins such as respiratory chain subunits or TIMM17A, a subunit of a protein translocase in the IM (Stiburek et al, 2012;Rainbolt et al, 2013).…”