Cristae Membrane Dynamics – A Paradigm Change

Abstract

Mitochondria are dynamic organelles that have essential metabolic and regulatory functions. Earlier studies using electron microscopy (EM) revealed an immense diversity in the architecture of cristaeinfoldings of the mitochondrial inner membrane (IM)in different cells, tissues, bioenergetic and metabolic conditions, and during apoptosis. However, cristae were considered to be largely static entities. Recently, advanced super-resolution techniques have revealed that cristae are independent bioenergetic units that are highly dynamic and remodel on a timescale of seconds. These advances, coupled with mechanistic and structural studies on key molecular players, such as the MICOS (mitochondrial contact site and cristae organizing system) complex and the dynamin-like GTPase OPA1, have changed our view on mitochondria in a fundamental way. We summarize these recent findings and discuss their functional implications. The Changing Paradigm of Mitochondrial IM Structure and Dynamics Mitochondria are double-membrane-enclosed organelles of endosymbiotic origin that harbor an outer membrane (OM) and an inner membrane (IM). The immense diversity of mitochondrial ultrastructures was elucidated by electron microscopy (EM) over recent decades, and various models of cristae organization have been put forward [1]. The use of 3D electron tomography (ET) in the 1990s to decipher cristae structure by Terry Frey and Carmen Mannella led to seminal contributions that mark a shift in our view on cristae organization [2-4]. Cristae were no longer seen as extended, broad infoldings of the IM but instead were connected to the inner boundary membrane (IBM; see Glossary) by pore-or slit-like structures called crista junctions (CJs) (Box 1). CJs were proposed to act as diffusion barriers for membrane and soluble proteins, metabolites, and even protons [4,5]. Later studies confirmed that the IM is indeed subcompartmentalized [6-8]. Despite these advances and the conception that cristae are variable in structure, cristae were considered to be static under a particular physiological condition. This view was certainly biased because mitochondrial ultrastructure was studied using EM at high spatial resolution, although in fixed sample specimens. The static nature of cristae was propagated in textbooks for the past 60 years. In the 1960s, Charles Hackenbrock observed that addition of ADP could reversibly change the IM connectivity coupled with changes in mitochondrial matrix volume in isolated rat liver mitochondria [9,10], and this was corroborated using 3D ET experiments almost three decades later [3,5,11]. The latter studies also led to the proposal that cristae membrane (CM) reorganization might involve membrane fusion and fission events [5]. In addition, induction of apoptosis was accompanied by changes in the IM shape, connectivity, and matrix volume [12], which strongly suggested that cristae can dynamically change their structure. Hence, there were clear indications that CM remodeling can be induced by altered physiological conditions. The us...

Organization of the Respiratory Supercomplexes in Cells with Defective Complex III: Structural Features and Metabolic Consequences

“…These ribbons of CV dimers are involved in the folding crista membrane [56]. It seems therefore that the intra-mitochondrial architecture is complex than initially believed, with MICOS, OPA1 and CV dimers playing a stru role, together with the abundance of non-bilayer cone-shaped phospholipids, such a diolipin and phosphatidylethanolamine [53,57,58].…”

MICOS and the mitochondrial inner membrane morphology – when things get out of shape

“…depletion results in increased CJ diameter, increased cytochrome c release from the ICS as well as a loss of membrane potential ( [64,67].In addition to this case, the right concentration of ions in the different compartments is essential for maintaining cellular homeostasis, for example by signalling and initiating cell death programs when required, this will be an essential problem of future studies.…”

“…Previous studies have shown an interplay of MICOS subunits and CL. It was demonstrated that CL is required for assembly of MIC27, which is a subunit of the MIC10 sub-complex and belongs to apolipoprotein family [67,86]. Localization of Mic27 and mitochondrial morphology was analyzed in wild type (WT) cells and cells lacking the mitochondrial CL synthesis enzyme, Crd1.…”

“…Importantly, disturbances of PE or CL synthesis results in aberrant IM morphologies in several organisms [167,168]. PE is required for the activity of complex III and the loss of PE results in decreased cristae length and abnormal cristae shape [67,169]. Mitochondrial PE Accepted Article concentrations depend on lipid transfer between OM and IM are likely to be modulated by the relative spatial positioning these two membranes.…”

“…complexes that are embedded in IM, rely on CL for its optimal function [175,176] [177,178]. BTHS in humans is characterised by swollen cristae, concentric stacks and highly interconnected cristae in cardiac muscle cells [67].…”