Mia40 and MINOS act in parallel with Ccs1 in the biogenesis of mitochondrial Sod1

Abstract

Superoxide dismutase 1 (Sod1) is a major superoxide-scavenging enzyme in the eukaryotic cell, and is localized in the cytosol and intermembrane space of mitochondria. Sod1 requires its specific chaperone Ccs1 and disulfide bond formation in order to be retained in the intermembrane space. Our study identified a pool of Sod1 that is present in the reduced state in mitochondria that lack Ccs1. We created yeast mutants with mutations in highly conserved amino acid residues corresponding to human mutations that cause amyotrophic lateral sclerosis, and found that some of the mutant proteins were present in the reduced state. These mutant variants of Sod1 were efficiently localized in mitochondria. Localization of the reduced, Ccs1-independent forms of Sod1 relied on Mia40, an essential component of the mitochondrial intermembrane space import and assembly pathway that is responsible for the biogenesis of intermembrane space proteins. Furthermore, the mitochondrial inner membrane organizing system (MINOS), which is responsible for mitochondrial membrane architecture, differentially modulated the presence of reduced Sod1 in mitochondria. Thus, we identified novel mitochondrial players that are possibly involved in pathological conditions caused by changes in the biogenesis of Sod1.

Proteomic and genetic analysis of the response of S. cerevisiae to soluble copper leads to improvement of the antimicrobial function of cellulosic copper nanoparticles

“…The region on chromosome XI between 74,608 and 92,505 (Fig S4D) contained ten genes, among which MNN4 , PEX1 , MIA40 , MST1 , and DHP2 encoded amino acid polymorphisms between S288c and YJM789. Mia40 works with other proteins for the maturation of the mitochondrial fraction of Sod1 46 . Sod1 is a major contributor to converting superoxides to hydrogen peroxide, which is further catalyzed into water and hydrogen 47 and is important for tolerance to metals, including copper 48 .…”

Mechanisms of mutant SOD1 induced mitochondrial toxicity in amyotrophic lateral sclerosis

“…Oxygen concentration critically influences cellular distribution of CCS and subsequently that of wtSOD1 whereas mutSOD1 appears to be able to escape this physiological regulation leading to mitochondrial accumulation of mutants also in the absence of CCS (Kawamata and Manfredi, 2008). Recently, it was demonstrated that reduced mutSOD1 enter the mitochondria via CCS-independent route involving MINOS and Mia40 (Varabyova et al, 2013; Figure 1, reaction IIIb). In accordance with the implications of the redox status of Cys residues in human SOD1 for its mitochondrial association, a variety of SOD1 mutants have been observed to possess susceptibility to the reduction of disulfide bonds in vitro (Tiwari and Hayward, 2003).…”

“…A mitochondrial import mechanism for SOD1 independent of CCS has been described in yeast (Varabyova et al, 2013). This utilizes the mitochondrial inner membrane organization system (MINOS) and involves also Mia40.…”

“…This utilizes the mitochondrial inner membrane organization system (MINOS) and involves also Mia40. Interestingly, reduced SOD1 was retained in the mitochondria of CCS null cells in yeast (Varabyova et al, 2013). In mammalian cells, CCS independent mitochondrial import and retention exists for mutSOD1 (Kawamata and Manfredi, 2008).…”

Oxidative protein biogenesis and redox regulation in the mitochondrial intermembrane space

“…This system is functionally equivalent to the periplasmic membrane protein chaperones SurA and Fkp (Alcock et al 2008) and, although the proteins have no homology at the level of their amino acid sequence, they share a common substrate binding recognition pattern. Additionally, there are cases of very specialised chaperone proteins, such as Ccs1 (Suzuki et al 2013; Varabyova et al 2013) which is thought to interact specifically with Sod1 and drive its import into the IMS, as well as the heme lyases, which play a role in the import of cytochrome c (Nargang et al 1988). …”