The mitochondrial contact site complex, a determinant of mitochondrial architecture

Abstract

Mitochondria are organelles with a complex architecture. They are bounded by an envelope consisting of the outer membrane and the inner boundary membrane (IBM). Narrow crista junctions (CJs) link the IBM to the cristae. OMs and IBMs are firmly connected by contact sites (CS). The molecular nature of the CS remained unknown. Using quantitative high-resolution mass spectrometry we identified a novel complex, the mitochondrial contact site (MICOS) complex, formed by a set of mitochondrial membrane proteins that is essential for the formation of CS. MICOS is preferentially located at the CJs. Upon loss of one of the MICOS subunits, CJs disappear completely or are impaired, showing that CJs require the presence of CS to form a superstructure that links the IBM to the cristae. Loss of MICOS subunits results in loss of respiratory competence and altered inheritance of mitochondrial DNA.

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 ).…”

“…These findings have prompted the hypothesis of a structural and functional connection between contact sites and crista junctions. The possibility of such an overlapping localization has been repeatedly addressed, although never comprehensively clarified (van der Klei et al , 1994 ;Perkins et al , 1997 ;Reichert and Neupert , 2002 ;Harner et al , 2011 ;K ö rner et al, 2012 ). Some studies have suggested that the integrity of crista junctions may depend on their anchoring to the outer mitochondrial membrane via mitofilin-containing contact sites (Harner et al , 2011 ;K ö rner et al, 2012 ;Ott 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 ). 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 ).…”

“…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.…”