Disrupted in Schizophrenia 1 (DISC1) is a Constituent of the Mammalian Mitochondrial Contact Site and Cristae Organizing System (MICOS) Complex, and is Essential for Oxidative Phosphorylation

Overview

Journal Hum Mol Genet

Specialties Genetics
Molecular Biology

Date 2016 Jul 29

PMID 27466199

Citations 25

Authors

Estefania Pinero-Martos

Bernardo Ortega-Vila

Josep Pol-Fuster

Eugenia Cisneros-Barroso

Laura Ruiz-Guerra

Aina Medina-Dols

Damian Heine-Suner

Jeronia Llado

Gabriel Olmos

Cristofol Vives-Bauza

Affiliations

Soon will be listed here.

Abstract

Disrupted in Schizophrenia-1 (DISC1) has been associated with a broad spectrum of mental disorders. DISC1 is a multi-compartmentalized protein found in the cytoplasm, centrosome, nuclei and mostly enriched in mitochondria. In order to shed light on DISC1 mitochondrial function, we have studied its topology within the organelle. We show in here that in mammals DISC1 resides in the 'Mitochondrial contact site and Cristae Organizing system' (MICOS) complex, involved in cristae organization. DISC1 knockdown in SH-SY5Y cells causes MICOS disassembly and fragmentation of the mitochondrial morphology network. Moreover, DISC1 depleted cells have decreased mitochondrial DNA (mtDNA) content and steady state levels of oxidative phosphorylation (OXPHOS) subunits. As a consequence, OXPHOS complexes and supercomplexes are partially disassembled in DISC1 knockdown cells, which suffer severe bioenergetic defects, evidenced by impaired oxygen consumption, adenosine triphosphate synthesis and mitochondrial membrane potential. Transfection of recombinant full-length human DISC1 restores MICOS complex assembly and rescues OXPHOS function, meanwhile overexpression of the DISC1 truncated form Δ597-854, known to be pathogenic, fails to rescue the bioenergetic impairment caused by DISC1 knockdown. These results should contribute to reveal DISC1 physiological function and potential pathogenic role in severe mental illnesses.

Citing Articles

Peering into the mind: unraveling schizophrenia's secrets using models.

Nani J, Muotri A, Hayashi M Mol Psychiatry. 2024; 30(2):659-678.

PMID: 39245692 DOI: 10.1038/s41380-024-02728-w.

Neikirk K, Kabugi K, Mungai M, Kula B, Smith N, Hinton Jr A J Cell Physiol. 2024; 239(8):e31317.

PMID: 38775168 PMC: 11324399. DOI: 10.1002/jcp.31317.

The serum small non-coding RNA (SncRNA) landscape as a molecular biomarker of age associated muscle dysregulation and insulin resistance in older adults.

Burton M, Antoun E, Garratt E, Westbury L, Dennison E, Harvey N FASEB J. 2024; 38(3):e23423.

PMID: 38294260 PMC: 10952661. DOI: 10.1096/fj.202301089RR.

Transcriptomic analysis reveals mitochondrial pathways associated with distinct adolescent behavioral phenotypes and stress response.

Santos-Silva T, Hazar Ulgen D, Lopes C, Guimaraes F, Alberici L, Sandi C Transl Psychiatry. 2023; 13(1):351.

PMID: 37978166 PMC: 10656500. DOI: 10.1038/s41398-023-02648-3.

3D reconstruction of murine mitochondria reveals changes in structure during aging linked to the MICOS complex.

Vue Z, Garza-Lopez E, Neikirk K, Katti P, Vang L, Beasley H Aging Cell. 2023; 22(12):e14009.

PMID: 37960952 PMC: 10726809. DOI: 10.1111/acel.14009.

References

Yang R, Sun L, Zhang R, Zhang Y, Luo Y, Zheng W . Suppression of Mic60 compromises mitochondrial transcription and oxidative phosphorylation. Sci Rep. 2015; 5:7990. PMC: 4303897. DOI: 10.1038/srep07990. View

Uversky V . The multifaceted roles of intrinsic disorder in protein complexes. FEBS Lett. 2015; 589(19 Pt A):2498-506. DOI: 10.1016/j.febslet.2015.06.004. View

Zerbes R, van der Klei I, Veenhuis M, Pfanner N, van der Laan M, Bohnert M . Mitofilin complexes: conserved organizers of mitochondrial membrane architecture. Biol Chem. 2012; 393(11):1247-61. DOI: 10.1515/hsz-2012-0239. View

Kirsty Millar J, James R, Christie S, Porteous D . Disrupted in schizophrenia 1 (DISC1): subcellular targeting and induction of ring mitochondria. Mol Cell Neurosci. 2005; 30(4):477-84. DOI: 10.1016/j.mcn.2005.08.021. View

Mao Y, Ge X, Frank C, Madison J, Koehler A, Doud M . Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling. Cell. 2009; 136(6):1017-31. PMC: 2704382. DOI: 10.1016/j.cell.2008.12.044. View

Odgren P, Toukatly G, Bangs P, Gilmore R, Fey E . Molecular characterization of mitofilin (HMP), a mitochondria-associated protein with predicted coiled coil and intermembrane space targeting domains. J Cell Sci. 1996; 109 ( Pt 9):2253-64. DOI: 10.1242/jcs.109.9.2253. View

Zerbes R, Hoss P, Pfanner N, van der Laan M, Bohnert M . Distinct Roles of Mic12 and Mic27 in the Mitochondrial Contact Site and Cristae Organizing System. J Mol Biol. 2016; 428(8):1485-92. DOI: 10.1016/j.jmb.2016.02.031. View

Strauss M, Hofhaus G, Schroder R, Kuhlbrandt W . Dimer ribbons of ATP synthase shape the inner mitochondrial membrane. EMBO J. 2008; 27(7):1154-60. PMC: 2323265. DOI: 10.1038/emboj.2008.35. View

Ogawa F, Malavasi E, Crummie D, Eykelenboom J, Soares D, Mackie S . DISC1 complexes with TRAK1 and Miro1 to modulate anterograde axonal mitochondrial trafficking. Hum Mol Genet. 2013; 23(4):906-19. PMC: 3900104. DOI: 10.1093/hmg/ddt485. View

10.

Koob S, Barrera M, Anand R, Reichert A . The non-glycosylated isoform of MIC26 is a constituent of the mammalian MICOS complex and promotes formation of crista junctions. Biochim Biophys Acta. 2015; 1853(7):1551-63. DOI: 10.1016/j.bbamcr.2015.03.004. View

11.

Blackwood D, Fordyce A, Walker M, St Clair D, Porteous D, Muir W . Schizophrenia and affective disorders--cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. Am J Hum Genet. 2001; 69(2):428-33. PMC: 1235314. DOI: 10.1086/321969. View

12.

Eykelenboom J, Briggs G, Bradshaw N, Soares D, Ogawa F, Christie S . A t(1;11) translocation linked to schizophrenia and affective disorders gives rise to aberrant chimeric DISC1 transcripts that encode structurally altered, deleterious mitochondrial proteins. Hum Mol Genet. 2012; 21(15):3374-86. PMC: 3392113. DOI: 10.1093/hmg/dds169. View

13.

Genin E, Plutino M, Bannwarth S, Villa E, Cisneros-Barroso E, Roy M . CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis. EMBO Mol Med. 2015; 8(1):58-72. PMC: 4718158. DOI: 10.15252/emmm.201505496. View

14.

Plecita-Hlavata L, Engstova H, Alan L, Spacek T, Dlaskova A, Smolkova K . Hypoxic HepG2 cell adaptation decreases ATP synthase dimers and ATP production in inflated cristae by mitofilin down-regulation concomitant to MICOS clustering. FASEB J. 2016; 30(5):1941-57. DOI: 10.1096/fj.201500176. View

15.

Xie J, Marusich M, Souda P, Whitelegge J, Capaldi R . 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. 2007; 581(18):3545-9. DOI: 10.1016/j.febslet.2007.06.052. View

16.

Davies K, Strauss M, Daum B, Kief J, Osiewacz H, Rycovska A . Macromolecular organization of ATP synthase and complex I in whole mitochondria. Proc Natl Acad Sci U S A. 2011; 108(34):14121-6. PMC: 3161574. DOI: 10.1073/pnas.1103621108. View

17.

Weber T, Koob S, Heide H, Wittig I, Head B, Van der Bliek A . APOOL is a cardiolipin-binding constituent of the Mitofilin/MINOS protein complex determining cristae morphology in mammalian mitochondria. PLoS One. 2013; 8(5):e63683. PMC: 3660581. DOI: 10.1371/journal.pone.0063683. View

18.

Ott C, Dorsch E, Fraunholz M, Straub S, Kozjak-Pavlovic V . Detailed analysis of the human mitochondrial contact site complex indicate a hierarchy of subunits. PLoS One. 2015; 10(3):e0120213. PMC: 4363703. DOI: 10.1371/journal.pone.0120213. View

19.

Huynen M, Muhlmeister M, Gotthardt K, Guerrero-Castillo S, Brandt U . Evolution and structural organization of the mitochondrial contact site (MICOS) complex and the mitochondrial intermembrane space bridging (MIB) complex. Biochim Biophys Acta. 2015; 1863(1):91-101. DOI: 10.1016/j.bbamcr.2015.10.009. View

20.

Hoppins S, Collins S, Cassidy-Stone A, Hummel E, DeVay R, Lackner L . A mitochondrial-focused genetic interaction map reveals a scaffold-like complex required for inner membrane organization in mitochondria. J Cell Biol. 2011; 195(2):323-40. PMC: 3198156. DOI: 10.1083/jcb.201107053. View