Snapshot: Mitochondrial Architecture Walter Neupert Max Planck Institute of Biochemistry, D-82152 Martinsried, Germany

SnapShot: Mitochondrial Architecture Walter Neupert Max Planck Institute of Biochemistry, D-82152 Martinsried, Germany

Protein (synonyms Deletion/Depletion Phenotypes Organism Topology Location & Interaction Partners and gene names) General Mitochondrial Architecture Fcj1 (Mitofilin, S. cerevisiae 1 TM domain; C-term in IMS and IBM & CJ; self-oligomerizes, Yeast are viable but exhibit altered Loss of CJ, altered cristae Aim28, Fmp13, N-term in the matrix. binds MICOS/MINOS/MitOS mtDNA inheritance and decreased structure, accumulation of YKR016W) components and Sam50, Tob38, respiratory growth. Mammals and cristae stacks and cristae Mitofilin Mammals Ugo1, Fzo1. worms exhibit increased ROS rims. Higher membrane IMMT-1, IMMT-2 C. elegans production and apoptosis. potential. Mos1 (Mcs10, S. cerevisiae 1 TM domain; C-term in CJ; subunit of MICOS/MINOS/ Yeast are viable but exhibit Loss of CJ and formation of Mio10, YC1057C-A) IMS, N-term in matrix. Highly MitOS complex. respiratory deficiency. cristae stacks. conserved in eukaryotes. Aim5 (Mcs12, S. cerevisiae 1 TM domain; C-term in IMS, CJ; subunit of MICOS/MINOS/ Yeast are viable but exhibit altered Reduced number of CJ and YBR262C) N-term in matrix. MitOS complex. mtDNA inheritance. stacked cristae. Aim13 S. cerevisiae N-myristoylation signal; CJ; subunit of MICOS/MINOS/ Altered inheritance of mtDNA Loss of cristae, fragmented (Mcs19,YFRO11C) associates with IMS side of IM. MitOS complex In animals, binds in yeast. Altered distribution of cristae, and aberrantly ChChd3 Mammals ChChd3/CHCH-3 has similar Mitofilin, OPA1, and SAM50. mitochondria, decreased organelle branched cristae. CHCH-3 C. elegans topology and myristoylation fusion, loss of mitofilin and OPA1 in signal only. mammals and worms. Aim37 (Mcs27, S. cerevisiae Yeast protein contains 2 TM CJ; subunit of MICOS/MINOS/ Yeast exhibit altered mtDNA Reduced number of CJ. YN100W) domains that anchor it in the IM MitOS complex. inheritance and temperature- Worms contain mitochondria MOMA-1 C. elegans with both N and C termini facing sensitive respiratory growth. of variable diameter with the IMS. Although MOMA-1 has swollen cristae. a similar overall structure, it is not similar at the sequence level and is found primarily in the OM. Mos2 (Mcs29, S. cerevisiae 2 TM domains, anchored in IM CJ; subunit of MICOS/MINOS/ Yeast are viable. Slightly reduced number Cristae Junctions (CJ) and Contact Sites (CS) Mio27, YGR235C) with N and C termini in IMS. MitOS complex. of CJ. Sam50 S. cerevisiae b-barrel OM protein. OM; binds Sam37, Sam35; Yeast are inviable; SAM/TOB (Tob55,YNL026W) binds the MICOS/MINOS/MitOS complex is essential for the Sam50 Mammals complex. biogenesis of the TOM complex, D. melanogaster which imports the vast majority of C. elegans mitochondrial proteins. Ugo1 (YDR470C) S. cerevisiae 3 TM domains, N-term in cytosol OM; forms dimers, binds MICOS/ Loss of mtDNA and ability to Fragmented mitochondria and C term in IMS. MINOS/MitOS complex and respire. that have few cristae and fusion proteins, Fzo1 and Mgm1. no CJs. Mgm1 S. cerevisiae l-Mgm1 is anchored in the IM IM and IMS; forms homo- Yeast exhibit decreased respiratory Fragmented and clustered OPA1 Mammals with 1 TM domain; GTPase oligomers and associates with growth and loss of mtDNA; animal mitochondria with aberrant dOpa1 D. melanogaster domain in IMS. l-Mgm1 is OM fusion proteins (Fzo1 and cells show increased apoptosis. cristae and altered CJs. eat-3 C. elegans processed into s-Mgm1, which Ugo1 in yeast and MFN1 and Swollen cristae, IM septae. associates with the IM and the MFN2 in animals). inner face of the OM.

F1Fo-ATP synthase S. cerevisiae F1Fo-ATP synthase is a main IM; required for oligomerization Decreased respiratory growth rate. Increased number of CJ

components Mammals structural element of cristae of the F1Fo-ATP synthase and and branched cristae with Subunit e (Tim11, formation. Subunit e and subunit associated with positive curvature an almost complete loss of

Atp21, YDR322C-A) g associate with the F1Fo-ATP of cristae membranes. cristae rims, formation of IM Subunit g (Atp20, synthase in IM. Each contain 1 septae. YPR020W) predicted TM domain. Mdm31 (YHR194W) S. cerevisiae Anchored in IM by 3 predicted IM; form large complexes, but not Synthetically lethal with each other Giant mitochondria with Mdm32 (YOR147W) TM domains. These proteins with each other. and with MMM1, MDM34, MDM10, low levels of cardiolipin and share a high degree of amino and MDM12. Unable to respire, phosphatidyl-ethanolamine, acid sequence similarity. lose mtDNA, exhibit decreased accumulate vesiculated IM. mitochondrial motility. Loss of cristae and CJ. She9 (Mdm33, S. cerevisiae Anchored in IM by 2 predicted IM; forms homo-oligomeric Yeast are viable. Giant, interconnected YDR393W) TM domains. complex ranging in size from 200 ring-shaped mitochondria, to 500 kDa. decreased matrix content. Mics1 Mammals Anchored in OM by 7 predicted OM; binds cytochrome c. Increased release of cytochrome c Mitochondria fragment and (C. elegans homolog) TM domains. and other apoptotic proteins. aggregate. Aberrant cristae. Mmm1 (YLLOO6W) S. cerevisiae Integral ER membrane protein, ER; binds Mdm10, Mdm12, and Viable but have diminished Large spherical mitochondria associates with cytoplasmic Mdm34 to form the ERMES respiratory growth and impaired with elongated and branched surface of mitochondria. complex. phospholipid biosynthesis. cristae, IM septae. Mdm12 (YOL009C) S. cerevisiae Associated with cytoplasmic ER and mito; binds Mdm10, Viable but have diminished Large spherical mitochondria surface of endoplasmic reticulum Mmm1, and Mdm34 to form the respiratory growth and impaired with elongated and branched and mitochondria. ERMES complex. phospholipid biosynthesis. cristae. IM septae. Mdm34 (Mmm2, S. cerevisiae Mdm34 is associated with the OM; bind each other, Mdm12, Viable but have diminished Large spherical mitochondria YGL219C), Mdm10 OM and Mdm10 is an integral and Mmm1 to facilitate formation respiratory growth and impaired with elongated and branched Mito-ER contacts Organelle dynamics and Cristae/CJ formation (YAL10C) b-barrel protein in the OM. of the ERMES complex. phospholipid biosynthesis. cristae. IM septae.

A B C D E F

Abbreviations: OM, outer membrane; IM, inner membrane; IMS, intermembrane space; IBM, inner boundary membrane; CJ, crista junction; CS, contact site; ERMES, ER mito encounter structure.

722 Cell 149, April 27, 2012 ©2012 Elsevier Inc. DOI 10.1016/j.cell.2012.04.010 See online version for legend and references. SnapShot: Mitochondrial Architecture Walter Neupert Max Planck Institute of Biochemistry, D-82152 Martinsried, Germany

Mitochondria are essential organelles that participate in a wide variety of cellular functions, including oxidative phosphorylation; intermediary metabolism; and synthesis of Fe-S clusters, heme, and certain phospholipids. Mitochondria also play an important role in apoptosis and are linked to a number of disorders such as diabetes, neurodegenerative diseases, cancer, and aging. Function and structure of mitochondria are intimately linked. Mitochondria contain two different membranes, the outer membrane (OM) and the inner membrane (IM). The OM forms a barrier to the cytosol. The IM can be divided into several different parts. The inner boundary membrane (IBM) is tightly attached to the OM, leaving a space—the intermembrane space that measures < 2–3 nm. OM and IBM can be viewed as a kind of envelope that separates the mitochondrial interior from the cytosol. Invaginations from the IBM, the cristae, extend from the IBM into the matrix space. The space enclosed by the cristae is the intracrista space. The cristae are connected to the IBM by the cristae junctions (CJ), narrow tube-like structures. A further general hallmark of mitochondrial architecture is the contact sites between OM and IBM. These structures become visible when the IM is made to contract. Then, sites of adhesion between both membranes become apparent. Little is known about these sites, and in fact, there may be different types of interactions. Contacts between OM and IBM exist for translocation of proteins from the cytosol into the matrix and IM and probably also for the transport of phospholipids. The protein translocases TOM in the OM, and TIM23/TIM22 in the IM cooperate to insert newly made proteins into the IBM, from which they can reach the cristae only via the CJ. Likewise, contacts have been observed that facilitate the exchange of ATP in the matrix versus ADP in the cytosol. Whereas the latter two types of interaction seem to be transient, the first type appears to be quite stable, as they survive osmotic and ultrasonic treatment of mitochondria. These contact sites (CS) are present mainly where the CJ meet the OM and appear to have a role in the construction and positioning of CJ. Mitochondria typically form extended networks throughout the cytosol, and their overall morphology is controlled by organelle fusion and fission. The ultrastructural organization of mitochondrial membranes varies considerably between mitochondria of different organisms, tissues, and cell types (see electron microscopy images reprinted with permission from Fawcett [1981]). The diversity of mitochondrial architecture reflecting the diversity of their metabolic functions is apparent when comparing mitochondria from pancreas (A), adrenal cortex (B), astrocytes (C), muscle (D), brown adipose tissue (E), and an Amoeba (F). Not surprisingly, aberrant mitochondrial shapes and ultrastructures are observed in pathological situations. Because disruptions in mitochondrial architecture are often linked to defects in respiration, the budding yeast Saccharomyces cerevisiae, which can live without an intact respiratory system, has been instrumental in identifying conserved complexes that promote mitochondrial architecture and ultrastructural organization. Recently, the composi- tion and potential function of the MICOS/MitOS/MINOS complex were reported in three separate publications. This large complex is comprised of at least six proteins and con- tributes to the following features of mitochondrial architecture: (1) tethering of cristae to OM; (2) shaping the narrow necks of CJ; (3) controlling in the lateral diffusion of membrane components between IBM and cristae; (4) regulating the fusion of cristae with the IBM; (5) transporting membrane lipids into and out of the IM. A similar complex with similar function was reported to exist in mammalians and worms, and its components are also included in the table. In addition to the components of the MICOS/MINOS/MitOS complex, the table lists a variety of proteins that have an important role in determining mitochondrial architecture.

References

Darshi, M., Mendiola, V.L., Mackey, M.R., Murphy, A.N., Koller, A., Perkins, G.A., Ellisman, M.H., and Taylor, S.S. (2011). ChChd3, an inner mitochondrial membrane protein, is essential for maintaining crista integrity and mitochondrial function. J. Biol. Chem. 286, 2918–2932.

Fawcett, D.W. (1981). The Cell, Second Edition (Philadelphia: W.B. Saunders).

Frezza, C., Cipolat, S., Martins de Brito, O., Micaroni, M., Beznoussenko, G.V., Rudka, T., Bartoli, D., Polishuck, R.S., Danial, N.N., De Strooper, B., and Scorrano, L. (2006). OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell 126, 177–189.

Harner, M., Körner, C., Walther, D., Mokranjac, D., Kaesmacher, J., Welsch, U., Griffith, J., Mann, M., Reggiori, F., and Neupert, W. (2011). The mitochondrial contact site complex, a determinant of mitochondrial architecture. EMBO J. 30, 4356–4370.

Head, B.P., Zulaika, M., Ryazantsev, S., and van der Bliek, A.M. (2011). A novel mitochondrial outer membrane protein, MOMA-1, that affects cristae morphology in Caenorhabditis elegans. Mol. Biol. Cell 22, 831–841.

Hoppins, S., Collins, S.R., Cassidy-Stone, A., Hummel, E., Devay, R.M., Lackner, L.L., Westermann, B., Schuldiner, M., Weissman, J.S., and Nunnari, J. (2011). A mitochondrial- focused genetic interaction map reveals a scaffold-like complex required for inner membrane organization in mitochondria. J. Cell Biol. 195, 323–340.

John, G.B., Shang, Y., Li, L., Renken, C., Mannella, C.A., Selker, J.M., Rangell, L., Bennett, M.J., and Zha, J. (2005). The mitochondrial inner membrane protein mitofilin controls cristae morphology. Mol. Biol. Cell 16, 1543–1554.

Rabl, R., Soubannier, V., Scholz, R., Vogel, F., Mendl, N., Vasiljev-Neumeyer, A., Körner, C., Jagasia, R., Keil, T., Baumeister, W., et al. (2009). Formation of cristae and crista junctions in mitochondria depends on antagonism between Fcj1 and Su e/g. J. Cell Biol. 185, 1047–1063.

Sesaki, H., and Jensen, R.E. (2001). UGO1 encodes an outer membrane protein required for mitochondrial fusion. J. Cell Biol. 152, 1123–1134. von der Malsburg, K., Müller, J.M., Bohnert, M., Oeljeklaus, S., Kwiatkowska, P., Becker, T., Loniewska-Lwowska, A., Wiese, S., Rao, S., Milenkovic, D., et al. (2011). Dual role of mitofilin in mitochondrial membrane organization and protein biogenesis. Dev. Cell 21, 694–707.

Wong, E.D., Wagner, J.A., Scott, S.V., Okreglak, V., Holewinske, T.J., Cassidy-Stone, A., and Nunnari, J. (2003). The intramitochondrial dynamin-related GTPase, Mgm1p, is a com- ponent of a protein complex that mediates mitochondrial fusion. J. Cell Biol. 160, 303–311.

Xie, J., Marusich, M.F., Souda, P., Whitelegge, J., and Capaldi, R.A. (2007). The mitochondrial inner membrane protein mitofilin exists as a complex with SAM50, metaxins 1 and 2, coiled-coil-helix coiled-coil-helix domain-containing protein 3 and 6 and DnaJC11. FEBS Lett. 581, 3545–3549.