Dual Role of Mitofilin in Mitochondrial Membrane Organization and Protein Biogenesis

Abstract

The mitochondrial inner membrane consists of two domains, inner boundary membrane and cristae membrane that are connected by crista junctions. Mitofilin/Fcj1 was reported to be involved in formation of crista junctions, however, different views exist on its function and possible partner proteins. We report that mitofilin plays a dual role. Mitofilin is part of a large inner membrane complex, and we identify five partner proteins as constituents of the mitochondrial inner membrane organizing system (MINOS) that is required for keeping cristae membranes connected to the inner boundary membrane. Additionally, mitofilin is coupled to the outer membrane and promotes protein import via the mitochondrial intermembrane space assembly pathway. Our findings indicate that mitofilin is a central component of MINOS and functions as a multifunctional regulator of mitochondrial architecture and protein biogenesis.

Mic60/Mitofilin determines MICOS assembly essential for mitochondrial dynamics and mtDNA nucleoid organization

“…Recently, several groups identified a large protein complex, MICOS complex (mitochondrial contact site and cristae organizing system; previously named MINOS, MitOS, Mitofilin or Fcj1 complex ), that has a crucial role in the formation of cristae junctions, contact sites to the outer membrane, and the organization of inner membrane. [10][11][12][13][14] In yeast, MICOS consists of at least six subunits: Mic60 (Fcj1), Mic10 (Mio10/Mcs10/Mos1), Mic19 (Aim13/Mcs19), Mic26 (Mio27/Mcs29/Mos2), Mic12 (Aim5/ Msc12) and Mic27 (Aim37/Mcs27). In mammals, five subunits of MICOS have already been identified, including Mic60 (Mitofilin/IMMT), Mic10 (MINOS1), Mic19 (CHCHD3/MINOS3), Mic25 (CHCHD6/CHCM1) and Mic27 (APOOL).…”

Mitofilin complexes: conserved organizers of mitochondrial membrane architecture

“…In human cells, mitofilin was found to interact with the sorting and assembly machinery of the outer membrane (SAM complex) that has a central role in the biogenesis of outer membrane proteins ( Figure 2B) (Xie et al , 2007 ;Darshi et al , 2011 ;Alkhaja et al , 2012 ;Ott et al , 2012 ). In yeast, interactions of mitofilincontaining protein complexes of the inner membrane with the SAM complex, the TOM complex, porin channels and Ugo1 have been reported (Figure 2A) (Harner et al , 2011 ;Hoppins et al , 2011 ;von der Malsburg et al , 2011 ;K ö rner et al, 2012 ;Zerbes et al , 2012 ). The interaction of mitofilin with the TOM complex was shown to support the import of precursor proteins into the intermembrane space via the mitochondrial intermembrane space assembly (MIA) machinery (von der Malsburg et al , 2011 ).…”

“…In yeast, interactions of mitofilincontaining protein complexes of the inner membrane with the SAM complex, the TOM complex, porin channels and Ugo1 have been reported (Figure 2A) (Harner et al , 2011 ;Hoppins et al , 2011 ;von der Malsburg et al , 2011 ;K ö rner et al, 2012 ;Zerbes et al , 2012 ). The interaction of mitofilin with the TOM complex was shown to support the import of precursor proteins into the intermembrane space via the mitochondrial intermembrane space assembly (MIA) machinery (von der Malsburg et al , 2011 ). Thus, mitofilin appears to be involved in the formation of both crista junctions and contact sites, two basic elements of mitochondrial membrane architecture.…”

“…The Saccharomyces cerevisiae mitofilin protein (also termed formation of crista junctions 1/Fcj1) was the first protein shown to be mainly located at crista junctions Harner et al , 2011 ). Depletion of mitofilin in human cells and worms or deletion of mitofilin in yeast leads to an extension of the inner membrane surface, a massive loss of crista junctions and to abnormal crista structures that appear as stacked lamellae disconnected from the inner boundary membrane (John et al , 2005 ;Rabl et al , 2009 ;Mun et al , 2010 ;Harner et al , 2011 ;Hoppins et al , 2011 ;von der Malsburg et al , 2011 ;Alkhaja et al , 2012 ). These observations point to a conserved function of mitofilin in the formation and/or maintenance of crista junctions.…”

“…Mitofilin possesses an N-terminal mitochondrial targeting sequence followed by a transmembrane segment and a large domain exposed to the intermembrane space. The intermembrane space domain consists of at least two defined subdomains: an extended putative coiled-coil region and a short C-terminal mitofilin signature domain von der Malsburg et al , 2011 ;K ö rner et al, 2012 ;Zerbes et al , 2012 ). Mitofilins are ubiquitous mitochondrial proteins that share this domain organization from yeast to humans, whereas the mitofilin signature domain is the only part of the protein that exhibits strong conservation at the primary structure level across species K ö rner et al, 2012 ;Zerbes et al , 2012 ).…”