Optic Atrophy 1 Is Epistatic to the Core MICOS Component MIC60 in Mitochondrial Cristae Shape Control

Christina Glytsou,Enrique Calvo,Sara Cogliati,Arpit Mehrotra,Irene Anastasia,Giovanni Rigoni,Andrea Raimondi,Norihito Shintani,Marta Loureiro,Jesùs Vazquez,Luca Pellegrini,Jose Antonio Enriquez,Luca Scorrano,Maria Eugenia Soriano

doi:10.1016/j.celrep.2016.11.049

Abstract

SummaryThe mitochondrial contact site and cristae organizing system (MICOS) and Optic atrophy 1 (OPA1) control cristae shape, thus affecting mitochondrial function and apoptosis. Whether and how they physically and functionally interact is unclear. Here, we provide evidence that OPA1 is epistatic to MICOS in the regulation of cristae shape. Proteomic analysis identifies multiple MICOS components in native OPA1-containing high molecular weight complexes disrupted during cristae remodeling. MIC60, a core MICOS protein, physically interacts with OPA1, and together, they control cristae junction number and stability, OPA1 being epistatic to MIC60. OPA1 defines cristae width and junction diameter independently of MIC60. Our combination of proteomics, biochemistry, genetics, and electron tomography provides a unifying model for mammalian cristae biogenesis by OPA1 and MICOS.

Highlights

The pleotropic roles of mitochondria in energy conversion, cell death, calcium homeostasis, intermediary metabolism, cell differentiation, and even immunity are matched by their morphological and ultrastructural complexity (Pernas and Scorrano, 2016)
Mitochondria are organized into five sub-compartments: outer membrane (OMM), intermembrane space (IMS), inner boundary membrane (IBM), cristae, and matrix (Cogliati et al, 2016)
MIC60 and Optic atrophy 1 (OPA1) Are Retrieved in the Same Complexes Targeted during Cristae Remodeling Cytochrome c is a key activator of programmed cell death in vertebrates, possibly explaining the recruitment of cristae remodeling and CJ proteins like OPA1 in this process at the onset of vertebrate evolution

Summary

Introduction

The pleotropic roles of mitochondria in energy conversion, cell death, calcium homeostasis, intermediary metabolism, cell differentiation, and even immunity are matched by their morphological and ultrastructural complexity (Pernas and Scorrano, 2016). Mitochondria are organized into five sub-compartments: outer membrane (OMM), intermembrane space (IMS), inner boundary membrane (IBM), cristae, and matrix (Cogliati et al, 2016). CJW increases during apoptosis, allowing cytochrome c redistribution from the lumen to the IMS (Große et al, 2016; Scorrano et al, 2002; Yamaguchi et al, 2008) Both CLW and CJW are controlled by the dynamin guanosine triphosphatase (GTPase) OPA1 (Cogliati et al, 2013; Frezza et al, 2006), independent of its role in mitochondrial fusion (Cipolat et al, 2004; Frezza et al, 2006). Increased apoptotic CLW and CJW correlates with destabilization of $720 kDa OPA1-containing complexes of unknown composition (Cogliati et al, 2013; Frezza et al, 2006; Varanita et al, 2015)

Results

Discussion

Conclusion