bims-cytox1 2021-10-10 papers

Issue of 2021–10–10
five papers selected by
Gavin McStay, Staffordshire University

Nat Rev Mol Cell Biol. 2021 Oct 07.

The assembly, regulation and function of the mitochondrial respiratory chain.

The mitochondrial oxidative phosphorylation system is central to cellular metabolism. It comprises five enzymatic complexes and two mobile electron carriers that work in a mitochondrial respiratory chain. By coupling the oxidation of reducing equivalents coming into mitochondria to the generation and subsequent dissipation of a proton gradient across the inner mitochondrial membrane, this electron transport chain drives the production of ATP, which is then used as a primary energy carrier in virtually all cellular processes. Minimal perturbations of the respiratory chain activity are linked to diseases; therefore, it is necessary to understand how these complexes are assembled and regulated and how they function. In this Review, we outline the latest assembly models for each individual complex, and we also highlight the recent discoveries indicating that the formation of larger assemblies, known as respiratory supercomplexes, originates from the association of the intermediates of individual complexes. We then discuss how recent cryo-electron microscopy structures have been key to answering open questions on the function of the electron transport chain in mitochondrial respiration and how supercomplexes and other factors, including metabolites, can regulate the activity of the single complexes. When relevant, we discuss how these mechanisms contribute to physiology and outline their deregulation in human diseases.

DOI: https://doi.org/10.1038/s41580-021-00415-0

J Inherit Metab Dis. 2021 Oct 05.

A simple mechanistic explanation for Barth syndrome and cardiolipin remodeling.

Yang Xu, Colin K L Phoon, Mindong Ren, Michael Schlame.

Barth syndrome is a multisystem disorder caused by an abnormal metabolism of the mitochondrial lipid cardiolipin. In this review, we discuss physical properties, biosynthesis, membrane assembly, and function of cardiolipin. We hypothesize that cardiolipin reduces packing stress in the inner mitochondrial membrane, which arises as a result of protein crowding. According to this hypothesis, patients with Barth syndrome are unable to meet peak energy demands because they fail to concentrate the proteins of oxidative phosphorylation to a high surface density in the inner mitochondrial membrane. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/jimd.12445

Mol Genet Metab. 2021 Sep 25. pii: S1096-7192(21)00781-2. [Epub ahead of print]

Variants in the MIPEP gene presenting with complex neurological phenotype without cardiomyopathy, impair OXPHOS protein maturation and lead to a reduced OXPHOS abundance in patient cells.

Juliette Pulman, Benedetta Ruzzenente, Martin Horak, Giulia Barcia, Nathalie Boddaert, Arnold Munnich, Agnès Rötig, Metodi D Metodiev.

Most mitochondrial proteins are synthesized in the cytosol and targeted to mitochondria via N-terminal mitochondrial targeting signals (MTS) that are proteolytically removed upon import. Sometimes, MTS removal is followed by a cleavage of an octapeptide by the mitochondrial intermediate peptidase (MIP), encoded by the MIPEP gene. Previously, MIPEP variants were linked to four cases of multisystemic disorder presenting with cardiomyopathy, developmental delay, hypotonia and infantile lethality. We report here a patient carrying compound heterozygous MIPEP variants-one was not previously linked to mitochondrial disease-who did not have cardiomyopathy and who is alive at the age of 20 years. This patient had developmental delay, global hypotonia, mild optic neuropathy and mild ataxia. Functional characterization of patient fibroblasts and HEK293FT cells carrying MIPEP hypomorphic alleles demonstrated that deficient MIP activity was linked to impaired post-import processing of subunits from four of the five OXPHOS complexes and decreased abundance and activity of some of these complexes in human cells possibly underlying the development of mitochondrial disease. Thus, our work expands the genetic and clinical spectrum of MIPEP-linked disease and establishes MIP as an important regulator of OXPHOS biogenesis and function in human cells.

Keywords: MIP; MIPEP; Mitochondrial disease; Mitochondrial intermediate peptidase; OXPHOS assembly defect; Protein processing

DOI: https://doi.org/10.1016/j.ymgme.2021.09.005

Nature. 2021 Oct 06.

Structure and assembly of the mammalian mitochondrial supercomplex CIII2CIV.

Irene Vercellino, Leonid A Sazanov.

The enzymes of the mitochondrial electron transport chain are key players of cell metabolism. Despite being active when isolated, in vivo they associate into supercomplexes1, whose precise role is debated. Supercomplexes CIII2CIV1-2 (refs. 2,3), CICIII2 (ref. 4) and CICIII2CIV (respirasome)5-10 exist in mammals, but in contrast to CICIII2 and the respirasome, to date the only known eukaryotic structures of CIII2CIV1-2 come from Saccharomyces cerevisiae11,12 and plants13, which have different organization. Here we present the first, to our knowledge, structures of mammalian (mouse and ovine) CIII2CIV and its assembly intermediates, in different conformations. We describe the assembly of CIII2CIV from the CIII2 precursor to the final CIII2CIV conformation, driven by the insertion of the N terminus of the assembly factor SCAF1 (ref. 14) deep into CIII2, while its C terminus is integrated into CIV. Our structures (which include CICIII2 and the respirasome) also confirm that SCAF1 is exclusively required for the assembly of CIII2CIV and has no role in the assembly of the respirasome. We show that CIII2 is asymmetric due to the presence of only one copy of subunit 9, which straddles both monomers and prevents the attachment of a second copy of SCAF1 to CIII2, explaining the presence of one copy of CIV in CIII2CIV in mammals. Finally, we show that CIII2 and CIV gain catalytic advantage when assembled into the supercomplex and propose a role for CIII2CIV in fine tuning the efficiency of electron transfer in the electron transport chain.

DOI: https://doi.org/10.1038/s41586-021-03927-z

J Inherit Metab Dis. 2021 Oct 09.

Cardiolipin function in the yeast S. cerevisiae and the lessons learned for Barth syndrome.

Jiajia Ji, Miriam L Greenberg.

Cardiolipin (CL) is the signature phospholipid (PL) of mitochondria and plays a pivotal role in mitochondrial and cellular function. Disruption of the CL remodeling gene tafazzin (TAZ) causes the severe genetic disorder Barth syndrome (BTHS). Our current understanding of the function of CL and the mechanism underlying the disease has greatly benefited from studies utilizing the powerful yeast model Saccharomyces cerevisiae. In this review, we discuss important findings on the function of CL and its remodeling from yeast studies and the implications of these findings for BTHS, highlighting the potential physiological modifiers that may contribute to the disparities in clinical presentation among BTHS patients. This article is protected by copyright. All rights reserved.

Keywords: Barth syndrome; Cardiolipin; mitochondrial disease; taffazzin; yeast

DOI: https://doi.org/10.1002/jimd.12447