Oma1, a Novel Membrane-bound Metallopeptidase in Mitochondria with Activities Overlapping with the m-AAA Protease

Abstract

The integrity of the inner membrane of mitochondria is maintained by a membrane-embedded quality control system that ensures the removal of misfolded membrane proteins. Two ATP-dependent AAA proteases with catalytic sites at opposite membrane surfaces are key components of this proteolytic system. Here we describe the identification of a novel conserved metallopeptidase that exerts activities overlapping with the m-AAA protease and was therefore termed Oma1. Both peptidases are integral parts of the inner membrane and mediate the proteolytic breakdown of a misfolded derivative of the polytopic inner membrane protein Oxa1. The m-AAA protease cleaves off the matrix-exposed C-terminal domain of Oxa1 and processively degrades its transmembrane domain. In the absence of the m-AAA protease, proteolysis of Oxa1 is mediated in an ATP-independent manner by Oma1 and a yet unknown peptidase resulting in the accumulation of N-and C-terminal proteolytic fragments. Oma1 exposes its proteolytic center to the matrix side; however, mapping of Oma1 cleavage sites reveals clipping of Oxa1 in loop regions at both membrane surfaces. These results identify Oma1 as a novel component of the quality control system in the inner membrane of mitochondria. Proteins homologous to Oma1 are present in higher eukaryotic cells, eubacteria and archaebacteria, suggesting that Oma1 is the founding member of a conserved family of membrane-embedded metallopeptidases.The majority of mitochondrial proteins is nuclear encoded and synthesized at cytosolic ribosomes. Import into mitochondria is mediated by various protein translocases in the outer and inner membrane that allow the passage of preproteins only in a largely unfolded conformation (1, 2). Folding and assembly of mitochondrial proteins must therefore occur inside mitochondria. Little is known about the efficiency of this process, but it is clear that mitochondria, as other organelles, harbor a quality control system that ensures the recognition and removal of non-native polypeptides, preventing their potentially harmful accumulation within the organelle (3). Notably, a functional impairment of components of this system leads to neurodegeneration in various forms of hereditary spastic paraplegia, illustrating the importance of protein quality control for mitochondrial function (4, 5).Molecular chaperone proteins and ATP-dependent proteases present in different subcompartments of mitochondria maintain protein quality control within the organelle (3). In line with the endosymbiotic origin of mitochondria, many of these components exhibit significant homology to bacterial proteins. ATP-dependent proteases homologous to Lon proteases (6 -8) and, at least in some organisms, Clp proteases (9, 10) have been identified in the mitochondrial matrix space, whereas the inner membrane harbors two AAA proteases homologous to bacterial FtsH proteases (11). These membrane-embedded peptidases were termed m-and i-AAA proteases to indicate their different topology in the inner membrane; the m-AAA protease is activ...

Proteolytic Activity of HtpX, a Membrane-bound and Stress-controlled Protease from Escherichia coli

“…This was consistent with the notion of membrane stress responses; abnormal membrane proteins are expected to be attacked from both sides of the membrane. Kaser et al (31) reported recently that a membrane-bound metalloprotease called Oma1 functions in the degradation of a mitochondrial membrane protein in conjunction with Yta10/12, a mitochondrial homolog of the FtsH protease. Unlike HtpX, Oma1 was reported to cleave a substrate membrane protein on both sides of the membrane.…”

Quality Control of Mitochondrial Proteostasis

“…Although some proteases appear to exert regulatory functions during mitochondrial biogenesis, a role for others in quality control is just emerging. These include the metallopeptidase Oma1, which was originally discovered in yeast to cleave a mutant IM protein in the absence of the m-AAA protease and was thus termed Oma1 because of its overlapping activity with the m-AAA protease (Käser et al 2003). Oma1 is evolutionarily conserved and is also found in higher eukaryotes, although a role in turnover/processing of misfolded proteins substrates has not yet been assigned.…”

Membrane depolarization activates the mitochondrial protease OMA 1 by stimulating self‐cleavage

“…OMA1 was identified in yeast as an ATP-independent zinc metalloprotease that locates at mitochondrial inner membrane and displays activities overlapping with a m-AAA protease [12]. OMA1 is a mitochondrial quality control protease and was reported as a new key regulator of metabolic homeostasis [13].…”