Cardiolipin puts the seal on ATP synthase

Mehdipour, Ahmad Reza; Hummer, Gerhard

doi:10.1073/pnas.1609806113

Cited by 28 publications

(30 citation statements)

References 22 publications

(25 reference statements)

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“…We propose that the DGS1 and NCA2 proteins play similar, but not identical, roles in yeast and plants for lipid import. This hypothesis is based on the fact that the decrease in ATP synthase in yeast is likely a secondary effect of an altered lipid composition, and CL may be a specific target that is required for the stability of the ATP synthase complex (Mehdipour and Hummer, 2016). To be noted, DGS1 and NCA2 also have specific functions.…”

Section: Discussionmentioning

confidence: 99%

Arabidopsis DGD1 SUPPRESSOR1 Is a Subunit of the Mitochondrial Contact Site and Cristae Organizing System and Affects Mitochondrial Biogenesis

Lavell

Meng

et al. 2019

The Plant Cell

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Mitochondrial and plastid biogenesis requires the biosynthesis and assembly of proteins, nucleic acids, and lipids. In Arabidopsis (Arabidopsis thaliana), the mitochondrial outer membrane protein DGD1 SUPPRESSOR1 (DGS1) is part of a large multi-subunit protein complex that contains the mitochondrial contact site and cristae organizing system 60-kD subunit, the translocase of outer mitochondrial membrane 40-kD subunit (TOM40), the TOM20s, and the Rieske FeS protein. A point mutation in DGS1, dgs1-1, altered the stability and protease accessibility of this complex. This altered mitochondrial biogenesis, mitochondrial size, lipid content and composition, protein import, and respiratory capacity. Whole plant physiology was affected in the dgs1-1 mutant as evidenced by tolerance to imposed drought stress and altered transcriptional responses of markers of mitochondrial retrograde signaling. Putative orthologs of Arabidopsis DGS1 are conserved in eukaryotes, including the Nuclear Control of ATP Synthase2 (NCA2) protein in yeast (Saccharomyces cerevisiae), but lost in Metazoa. The genes encoding DGS1 and NCA2 are part of a similar coexpression network including genes encoding proteins involved in mitochondrial fission, morphology, and lipid homeostasis. Thus, DGS1 links mitochondrial protein and lipid import with cellular lipid homeostasis and whole plant stress responses.

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Section: Discussionmentioning

confidence: 99%

Arabidopsis DGD1 SUPPRESSOR1 Is a Subunit of the Mitochondrial Contact Site and Cristae Organizing System and Affects Mitochondrial Biogenesis

Lavell

Meng

et al. 2019

The Plant Cell

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“…The CV dimer is thought to be essential to the formation of cristae by bending the IMM [51]. ATP synthase function depends on CL, which binds specifically, yet intermittently, to the IMM embedded c-ring portion of CV in the F0 region, acting as a lubricant for rotation of the CV rotor [10,52,53]. CV localizes near the tightly curved ends of cristae, where it assembles as rows of dimers stabilizing the IMM curvature [54][55][56].…”

Section: Atp Production and Transport (Cv Ck And Adt)mentioning

confidence: 99%

“…Bound CL molecules are required for the enzymatic activities and stabilities of both individual protein subunits and protein supercomplexes involved in mitochondrial respiration. For example, CL plays an essential role in the oligomerization of the c-rings and lubrication of its rotation in ATP synthase (CV), which can influence the stability of cristae structure through dimerization [9,10]; CL acts as glue holding respiratory supercomplexes (CIII and CIV) together and steering their assembly and organization [11,12]; the binding sites of CL identified close to the proton transfer pathway in CIII and CIV suggest a role of CL in proton uptake through the IMM [13][14][15]. In the case of the ADP/ATP translocase, ADT, three bound CL molecules securely anchor the carrier protein in the IMM and affect ADP/ATP transport activity [16].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial protein interaction landscape of SS-31

Chavez

Tang

Campbell

et al. 2019

Preprint

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Mitochondrial dysfunction underlies the etiology of a broad spectrum of diseases including heart disease, cancer, neurodegenerative diseases, and the general aging process. Therapeutics that restore healthy mitochondrial function hold promise for treatment of these conditions. The synthetic tetrapeptide, elamipretide (SS-31), improves mitochondrial function, but mechanistic details of its pharmacological effects are unknown. Reportedly, SS-31 primarily interacts with the phospholipid cardiolipin in the inner mitochondrial membrane. Here we utilize chemical cross-linking with mass spectrometry to identify protein interactors of SS-31 in mitochondria. The SS-31-interacting proteins, all known cardiolipin binders, fall into two groups, those involved in ATP production through the oxidative phosphorylation pathway and those involved in 2-oxoglutarate metabolic processes. Residues cross-linked with SS-31 reveal binding regions that in many cases, are proximal to cardiolipin-protein interacting regions. These results offer the first glimpse of the protein interaction landscape of SS-31 and provide new mechanistic insight relevant to SS-31 mitochondrial therapy. Significance StatementSS-31 is a synthetic peptide that improves mitochondrial function and is currently undergoing clinical trials for treatments of heart failure, primary mitochondrial myopathy, and other mitochondrial diseases. SS-31 interacts with cardiolipin which is abundant in the inner mitochondrial membrane, but mechanistic details of its pharmacological effects are unknown. Here we apply a novel chemical cross-linking/mass spectrometry method to provide the first direct evidence for specific interactions between SS-31 and mitochondrial proteins. The identified SS-31 interactors are functional components in ATP production and 2-oxoglutarate metabolism and signaling, consistent with improved mitochondrial function resultant from SS-31 treatment. These results offer the first glimpse of the protein interaction landscape of SS-31 and provide new mechanistic insight relevant to SS-31 mitochondrial therapy.

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“…Thus, it is not surprising that CL has been found to selectively interact with succinate dehydrogenase and F o F 1 ATP-synthase [ 173 , 174 ]. Indeed, it was recently demonstrated that the mitochondrial F o F 1 ATP-synthase possesses a CL interaction site, conserved between yeast and bovine, which is enriched in positively charged amino acids [ 175 , 176 ].…”

Section: Influence Of Membrane Curvature On Phospholipid Biosynthesismentioning

confidence: 99%

Inducible intracellular membranes: molecular aspects and emerging applications

et al. 2020

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Membrane remodeling and phospholipid biosynthesis are normally tightly regulated to maintain the shape and function of cells. Indeed, different physiological mechanisms ensure a precise coordination between de novo phospholipid biosynthesis and modulation of membrane morphology. Interestingly, the overproduction of certain membrane proteins hijack these regulation networks, leading to the formation of impressive intracellular membrane structures in both prokaryotic and eukaryotic cells. The proteins triggering an abnormal accumulation of membrane structures inside the cells (or membrane proliferation) share two major common features: (1) they promote the formation of highly curved membrane domains and (2) they lead to an enrichment in anionic, cone-shaped phospholipids (cardiolipin or phosphatidic acid) in the newly formed membranes. Taking into account the available examples of membrane proliferation upon protein overproduction, together with the latest biochemical, biophysical and structural data, we explore the relationship between protein synthesis and membrane biogenesis. We propose a mechanism for the formation of these non-physiological intracellular membranes that shares similarities with natural inner membrane structures found in α-proteobacteria, mitochondria and some viruses-infected cells, pointing towards a conserved feature through evolution. We hope that the information discussed in this review will give a better grasp of the biophysical mechanisms behind physiological and induced intracellular membrane proliferation, and inspire new applications, either for academia (high-yield membrane protein production and nanovesicle production) or industry (biofuel production and vaccine preparation).

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Cardiolipin puts the seal on ATP synthase

Cited by 28 publications

References 22 publications

Arabidopsis DGD1 SUPPRESSOR1 Is a Subunit of the Mitochondrial Contact Site and Cristae Organizing System and Affects Mitochondrial Biogenesis

Arabidopsis DGD1 SUPPRESSOR1 Is a Subunit of the Mitochondrial Contact Site and Cristae Organizing System and Affects Mitochondrial Biogenesis

Mitochondrial protein interaction landscape of SS-31

Inducible intracellular membranes: molecular aspects and emerging applications

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