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Cardiolipin remodeling enables protein crowding in the inner mitochondrial membrane

ABSTRACT: Mitochondrial cristae are more crowded with proteins than other cellular membranes. However, protein crowding stresses the bilayer organization of lipids, which challenges membrane stability. We tested the hypothesis that the high concentration of proteins drives the tafazzin-catalyzed remodeling of fatty acids in cardiolipin (CL) to reduce stress on the lipid bilayer

INSTRUMENT(S): Q Exactive HF, Q Exactive

ORGANISM(S): Drosophila Melanogaster (ncbitaxon:7227) Saccharomyces Cerevisiae (ncbitaxon:4932) Mus Musculus (ncbitaxon:10090)

SUBMITTER: Dr. Thomas A. Neubert Dr. Michael Schlame

PROVIDER: MSV000087602 | MassIVE | Thu Jun 10 08:43:00 BST 2021

SECONDARY ACCESSION(S): PXD026620

REPOSITORIES: MassIVE

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Cardiolipin is required for membrane docking of mitochondrial ribosomes and protein synthesis

Project description:The mitochondrial inner membrane contains a unique phospholipid known as cardiolipin (CL), which stabilises the protein complexes embedded in the membrane and supports its overall structure. Recent evidence indicates that the mitochondrial ribosome may associate with the inner membrane to facilitate co-translational insertion of the hydrophobic oxidative phosphorylation (OXPHOS) proteins into the inner membrane. We generated three mutant knockout cell lines for the cardiolipin biosynthesis gene Crls1 to investigate the effects of cardiolipin loss on mitochondrial protein synthesis. Reduced CL levels caused altered mitochondrial morphology and transcriptome-wide changes that were accompanied by reduced uncoordinated mitochondrial translation rates and impaired respiratory supercomplex formation. Aberrant protein synthesis was caused by impaired formation and distribution of mitochondrial ribosomes. Reduction or loss of cardiolipin resulted in resulted in different mitochondrial and endoplasmic reticulum stress responses. We show that cardiolipin is required to stabilise the interaction of the mitochondrial ribosome with the membrane via its association with OXA1 during active translation. This interaction facilitates insertion of newly synthesised mitochondrial proteins into the inner membrane and stabilises the respiratory supercomplexes.

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Defective mitochondrial cardiolipin remodeling dampens HIF-1a expression in hypoxia

Project description:Mitochondria fulfill vital metabolic functions and act as crucial cellular signaling hubs integrating their metabolic status into the cellular context. Here, we show that defective cardiolipin-remodeling, upon loss of the cardiolipin acyl transferase Tafazzin, mutes HIF-1a signaling in hypoxia. Tafazzin-deficiency does not affect posttranslational HIF-1a regulation but rather HIF-1a gene-expression, a dysfunction recapitulated in iPSCs-derived cardiomyocytes from Barth Syndrome patients with Tafazzin-deficiency. RNAseq analyses confirmed drastically altered signaling in Tafazzin mutant cells. In hypoxia, Tafazzin-deficient cells display reduced production of reactive oxygen species (ROS) perturbing NF-kB activation and concomitantly HIF-1a gene-expression. In agreement, Tafazzin-deficient mice hearts display reduced HIF-1a levels and undergo maladaptive hypertrophy with heart failure in response to pressure overload challenge. We conclude that defective mitochondrial cardiolipin-remodeling dampens HIF-1a signaling through inactivation of a non-canonical signaling pathway: Lack of NF-kB activation through reduced mitochondrial ROS production diminishes HIF-1a transcription.

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Re-expression of tafazzin isoforms in TAZ-deficient C6 glioma cells restores cardiolipin composition but not proliferation rate and alterations in gene expression

Project description:Tafazzin an acyltransferase is involved in cardiolipin (CL) remodeling. CL is associated with mitochondrial function, structure and more recently with cell proliferation. Various tafazzin isoforms exists in humans. The role of these isoforms in cardiolipin remodeling is unknown. Aim of this study is to investigate if isoform Δ5, which is lacking exon 5, full length rat TAZ, and mutant full-length rat Taz (enzymatically dead H69L) could restore wild type phenotype in C6 TAZ cells with respect to CL composition, cellular proliferation and gene expression profile. In addition, we aim to determine the molecular mechanism by which tafazzin can modulate gene expression by applying promoter analysis and IPA to genes regulated by TAZ-deficiency. Expression of Δ5 and rat full length TAZ in C6-TAZ- cells can fully restore CL composition and – as proven for 5 – this is naturally associated with restoration of mitochondrial respiration. A similar restoration of CL-composition could not be observed after re-expression of an enzymatically dead full-length rat TAZ (H69L; TAZmut3). The re-expression of none of the TAZ isoforms used led to the restoration of the proliferation rate and gene expression profiles. Very likely TAZ-deficiency provokes substantial long-lasting changes in cellular lipid metabolism which contribute to changes in proliferation and gene expression, and are not or only very slowly reversible.

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Cardiolipin Synthesis Governs Systemic Energy Homeostasis through Thermogenic Fat Mitochondria

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Deacylation on the matrix side of the mitochondrial inner membrane regulates cardiolipin remodeling.

Project description:The mitochondrial-specific lipid cardiolipin (CL) is required for numerous processes therein. After its synthesis on the matrix-facing leaflet of the inner membrane (IM), CL undergoes acyl chain remodeling to achieve its final form. In yeast, this process is completed by the transacylase tafazzin, which associates with intermembrane space (IMS)-facing membrane leaflets. Mutations in TAZ1 result in the X-linked cardiomyopathy Barth syndrome. Amazingly, despite this clear pathophysiological association, the physiological importance of CL remodeling is unresolved. In this paper, we show that the lipase initiating CL remodeling, Cld1p, is associated with the matrix-facing leaflet of the mitochondrial IM. Thus monolysocardiolipin generated by Cld1p must be transported to IMS-facing membrane leaflets to gain access to tafazzin, identifying a previously unknown step required for CL remodeling. Additionally, we show that Cld1p is the major site of regulation in CL remodeling; and that, like CL biosynthesis, CL remodeling is augmented in growth conditions requiring mitochondrially produced energy. However, unlike CL biosynthesis, dissipation of the mitochondrial membrane potential stimulates CL remodeling, identifying a novel feedback mechanism linking CL remodeling to oxidative phosphorylation capacity.

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