Regulation of mitochondrial phospholipids by Ups1/PRELI-like proteins depends on proteolysis and Mdm35

Abstract

The mitochondrial phospholipid metabolism critically depends on members of the conserved Ups1/PRELI-like protein family in the intermembrane space. Ups1 and Ups2 (also termed Gep1) were shown to regulate the accumulation of cardiolipin (CL) and phosphatidylethanolamine (PE), respectively, in a lipid-specific but coordinated manner. It remained enigmatic, however, how the relative abundance of both phospholipids in mitochondrial membranes is adjusted on the molecular level. Here, we describe a novel regulatory circuit determining the accumulation of Ups1 and Ups2 in the intermembrane space. Ups1 and Ups2 are intrinsically unstable proteins, which are degraded by distinct mitochondrial peptidases. The turnover of Ups2 is mediated by the i-AAA protease Yme1, whereas Ups1 is degraded by both Yme1 and the metallopeptidase Atp23. We identified Mdm35, a member of the twin Cx 9 C protein family, as a novel interaction partner of Ups1 and Ups2. Binding to Mdm35 ensures import and protects both proteins against proteolysis. Homologues to all components of this pathway are present in higher eukaryotes, suggesting that the regulation of mitochondrial CL and PE levels is conserved in evolution.

Mitochondrial protein homeostasis

“…More recently, the IMS resident Mdm35 was shown to serve as a folding and assembly trap for the Ups proteins, Ups1 and Ups2, which function in lipid transfer (70). These two examples support the folding trap model for IMS proteins based on retention of proteins within the IMS through folding.…”

“…Both the i-AAA and m-AAA proteases extract proteins from the membranes for degradation but also cleave both soluble IMS and matrix substrates, respectively. For instance, when IMS proteins such as the small Tim proteins (involved in protein transport) or Ups proteins (involved in lipid transfer) fail to properly fold or assemble, their removal is mediated by the i-AAA protease (70,104). These findings demonstrate the necessity to clear immature proteins in the crowded mitochondrial compartments.…”

Loss of Drosophila i-AAA protease, dYME1L, causes abnormal mitochondria and apoptotic degeneration

“…In yeast, the mitochondrial i-AAA protease is also required for the turnover of Ups1 and Ups2, which regulate the accumulation of cardiolipin (CL) and phosphatidylethanolamine, respectively. 55 Thus, impaired phospholipid metabolism might be another inroad leading to the membrane remodeling, rupture and eventually apoptosis in mitochondrial i-AAA protease mutant flies (Supplementary Figure S7). Our results not only support that mitochondrial disruption per se could trigger apoptosis in Drosophila but also suggest that apoptotic neuronal death might be a common degenerative mechanism associated with mitochondrial AAA protease mutations.…”

Quality Control of Mitochondrial Proteostasis

“…Yeast Atp23 acts not only as a peptidase for the maturation of Atp6 but also as a chaperone for its assembly into the F 1 F O -ATP synthase (Osman et al 2007;Zeng et al 2007). More recently, Atp23 was also shown to play a role in concert with Yme1 in the turnover of Ups1 (Potting et al 2010). Although a mammalian Atp23 homolog does exist, its function remains uncharacterized.…”

“…Cite this article as Cold Spring Harb Perspect Biol 2011;3:a007559 phospholipid levels, Ups1 and Ups2 (Potting et al 2010). Both proteins are intrinsically unstable and degraded by Yme1 under physiological conditions, controlling their accumulation within mitochondria.…”