MICOS assembly controls mitochondrial inner membrane remodeling and crista junction redistribution to mediate cristae formation.

Till Stephan,Markus Deckers,Stefan Jakobs,Stefan Stoldt,Christian Brüser,Wolfgang Hübner,Wiebke Möbius,Dietmar Riedel,Thomas Huser,Peter Ilgen,Francisco Balzarotti,Gudrun Heim,Peter Rehling,Mariam Barbot,Tiana S Behr,Jasmin K Pape ,Stefan W Hell ,David Pacheu-Grau ,F De Lange ,Anna M Steyer

doi:10.15252/embj.2019104105

Abstract

Mitochondrial function is critically dependent on the folding of the mitochondrial inner membrane into cristae; indeed, numerous human diseases are associated with aberrant crista morphologies. With the MICOS complex, OPA1 and the F1Fo‐ATP synthase, key players of cristae biogenesis have been identified, yet their interplay is poorly understood. Harnessing super‐resolution light and 3D electron microscopy, we dissect the roles of these proteins in the formation of cristae in human mitochondria. We individually disrupted the genes of all seven MICOS subunits in human cells and re‐expressed Mic10 or Mic60 in the respective knockout cell line. We demonstrate that assembly of the MICOS complex triggers remodeling of pre‐existing unstructured cristae and de novo formation of crista junctions (CJs) on existing cristae. We show that the Mic60‐subcomplex is sufficient for CJ formation, whereas the Mic10‐subcomplex controls lamellar cristae biogenesis. OPA1 stabilizes tubular CJs and, along with the F1Fo‐ATP synthase, fine‐tunes the positioning of the MICOS complex and CJs. We propose a new model of cristae formation, involving the coordinated remodeling of an unstructured crista precursor into multiple lamellar cristae.

Highlights

Mitochondrial function is critically dependent on the folding of the mitochondrial inner membrane into cristae; numerous human diseases are associated with aberrant crista morphologies
Live-cell 2D stimulated emission depletion (STED) nanoscopy of HeLa cells stably expressing cytochrome c oxidase subunit 8A (COX8A) C-terminally fused with a SNAP-tag revealed that these cells predominantly exhibit groups of lamellar cristae spaced by voids that are occupied by mitochondrial nucleoids (Fig 1A and C) (Stephan et al, 2019)
We investigated the interplay of the major determinants of cristae formation in higher eukaryotes, namely the Mic10 and the Mic60 subcomplexes of MItochondrial contact site and Cristae Organizing System (MICOS), optic atrophy 1 (OPA1), and the F1Fo-ATP synthase

Summary

Introduction

Mitochondrial function is critically dependent on the folding of the mitochondrial inner membrane into cristae; numerous human diseases are associated with aberrant crista morphologies. With the MICOS complex, OPA1 and the F1Fo-ATP synthase, key players of cristae biogenesis have been identified, yet their interplay is poorly understood. We individually disrupted the genes of all seven MICOS subunits in human cells and re-expressed Mic or Mic in the respective knockout cell line. We demonstrate that assembly of the MICOS complex triggers remodeling of pre-existing unstructured cristae and de novo formation of crista junctions (CJs) on existing cristae. We show that the Mic60-subcomplex is sufficient for CJ formation, whereas the Mic10-subcomplex controls lamellar cristae biogenesis. OPA1 stabilizes tubular CJs and, along with the F1Fo-ATP synthase, fine-tunes the positioning of the MICOS complex and CJs. We propose a new model of cristae formation, involving the coordinated remodeling of an unstructured crista precursor into multiple lamellar cristae

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