Cardiolipin mediates membrane and channel interactions of the mitochondrial TIM23 protein import complex receptor Tim50

Malhotra, Ketan; Modak, Arnab; Nangia, Shivangi; Daman, Tyler; Günsel, Umut; Robinson, Victoria; Mokranjac, Dejana; May, Eric R.; Alder, Nathan N.

doi:10.1126/sciadv.1700532

Cited by 52 publications

(47 citation statements)

References 125 publications

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“…We used atomistic MD simulations to investigate the CL-dependent properties in ternary lipid bilayer systems composed of PC, PE, and CL; the CL content encompassed the natural range found in mitochondrial membranes, including the inner and outer mitochondrial membrane and their contact sites. From these simulations, we estimated a variety of membrane properties known to influence the energy and kinetics of protein-membrane and protein-protein interactions at membranes ( 93 , 117 ) and consequently affect membrane-protein properties such as conformation ( 98 , 104 , 118 , 119 , 120 ), activity ( 121 , 122 , 123 , 124 ), and distribution ( 101 , 103 ). Our analysis suggested that CL plays a minor role in altering membrane structural features in ternary lipid bilayers with a background matrix of PC and PE lipids but significantly alters lipid diffusion and thus bilayer fluidity.…”

Section: Discussionmentioning

confidence: 99%

Cardiolipin-Dependent Properties of Model Mitochondrial Membranes from Molecular Simulations

Wilson

Ramanathan

López

2019

Biophysical Journal

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Cardiolipin is an anionic lipid found in the mitochondrial membranes of eukaryotes ranging from unicellular microorganisms to metazoans. This unique lipid contributes to various mitochondrial functions, including metabolism, mitochondrial membrane fusion and/or fission dynamics, and apoptosis. However, differences in cardiolipin content between the two mitochondrial membranes, as well as dynamic fluctuations in cardiolipin content in response to stimuli and cellular signaling events, raise questions about how cardiolipin concentration affects mitochondrial membrane structure and dynamics. Although cardiolipin's structural and dynamic roles have been extensively studied in binary mixtures with other phospholipids, the biophysical properties of cardiolipin in higher number lipid mixtures are still not well resolved. Here, we used molecular dynamics simulations to investigate the cardiolipin-dependent properties of ternary lipid bilayer systems that mimic the major components of mitochondrial membranes. We found that changes to cardiolipin concentration only resulted in minor changes to bilayer structural features but that the lipid diffusion was significantly affected by those alterations. We also found that cardiolipin position along the bilayer surfaces correlated to negative curvature deflections, consistent with the induction of negative curvature stress in the membrane monolayers. This work contributes to a foundational understanding of the role of cardiolipin in altering the properties in ternary lipid mixtures composed of the major mitochondrial phospholipids, providing much-needed insights to help understand how cardiolipin concentration modulates the biophysical properties of mitochondrial membranes. SIGNIFICANCE Cardiolipin is an intrinsic component of the lipid milieu that makes up the membranes of eukaryotic mitochondria, and the distinctive lipid plays roles in both mitochondrial structure and function. Despite the many studies that establish that cardiolipin has unique properties in membranes, there are still questions about how much cardiolipin directly contributes to structural differences between the inner and outer mitochondrial membranes, as well as questions about how natural fluctuations in cardiolipin concentration alter the structure and dynamics of mitochondrial membranes. This study provides quantitative predictions for cardiolipin-dependent properties of lipid bilayer systems that mimic the major components of mitochondrial membranes. As such, it provides further insights into cardiolipin's role in modulating the biophysical properties of mitochondrial membranes.

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Section: Discussionmentioning

confidence: 99%

Cardiolipin-Dependent Properties of Model Mitochondrial Membranes from Molecular Simulations

Wilson

Ramanathan

López

2019

Biophysical Journal

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“…Liquid chromatography-tandem MS (LC-MS/MS) analysis of the 400-kDa SCC complex showed the presence of VDAC2 and Tim50, suggesting that SCC interacts directly with Tim50 at the IMM. Tim50 is part of the TIM23 complex consisting of a large globular receptor domain in the IMS, where it assembled in a highly dynamic manner through multiple potential interactive sites (26), forming a complex with SCC. SDS-PAGE analysis of samples without or with PK treatment or staining with COX IV confirmed the same amount of protein present in each reaction (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We hypothesize that following insertion of the SCC 20 amino acids from the C terminus in the TIM23 complex, the protein is independently involved in interaction with Tim50, possibly forming an essential component for hydrogen bond formation with a hydroxyl group in the nearest neighbor (32). We next analyzed the possible sites of interaction between SCC and Tim50, including amino acids 141 to 146 in ␣5 of SCC and S164, L165, A166, T167, and G168 in the loop region of Tim50 (26). We mutated the small glycine and serine to the bulky charged amino acid arginine, generating the S164R and G168R Tim50 mutants.…”

Section: Resultsmentioning

confidence: 99%

Inner Mitochondrial Translocase Tim50 Is Central in Adrenal and Testicular Steroid Synthesis

Bose

Gebrail

Marshall³

et al. 2019

Molecular and Cellular Biology

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Adrenal and gonadal mitochondrial metabolic activity requires electrons from cofactors, cholesterol, and a substrate for rapid steroid synthesis, an essential requirement for mammalian survival. Substrate activity depends on its environment, which is regulated by chaperones and mitochondrial translocases. Cytochrome P450 side-chain cleavage enzyme (SCC or CYP11A1) catalyzes cholesterol to pregnenolone conversion, although its mechanism of action is not well understood. We find that SCC is directly imported into the mitochondrial matrix, where its N-terminal sequence is cleaved sequentially, after which it becomes activated following the second cleavage, which is dependent on the folding of the protein. Following integration of the SCC C terminus into the TIM23 complex, amino acids 141 to 146 interact with the intermembrane-exposed Tim50 protein, forming a large complex. The absence of Tim50 or its mutation reduced enzymatic activity. For the first time, we report that a protein activated at the matrix remains mostly unfolded and is transported back to the IMS to integrate with the TIM23 translocase complex and align with the Tim50 protein. Amino acid changes that suppress the association of Tim50 with SCC ablate metabolic activity. Thus, the TIM23 complex is the central regulator of metabolism guided by Tim50.

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“…From this series of simulations we estimated a variety of membrane properties, including structural quantities, mechanical moduli, and lipid diffusion. The properties we have characterized are known to influence the energy and kinetics of protein-membrane and protein-protein interactions at membranes (63,64), and consequently affect membrane protein properties such as conformation (52)(53)(54)(55)(56), activity (57)(58)(59)(60), and distribution (61,62).…”

Section: Discussionmentioning

confidence: 99%

“…There is ample evidence that membrane material properties (lipid packing, thickness, fluidity, etc.) play key roles in the function of membrane proteins, affecting their conformation (52)(53)(54)(55)(56), activity (57)(58)(59)(60), and distribution (61,62). These properties modulate the landscape of interactions primarily through their effects on the energy and kinetics of protein-membrane and protein-protein interactions at the membrane (63,64).…”

Section: Introductionmentioning

confidence: 99%

Cardiolipin-Dependent Properties of Model Mitochondrial Membranes from Molecular Dynamics Simulations

Wilson

Ramanathan

López

2019

Preprint

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Cardiolipin is a unique anionic lipid found in mitochondrial membranes where it contributes to various mitochondrial functions, including metabolism, mitochondrial membrane fusion/fission dynamics, and apoptosis. Dysregulation of cardiolipin synthesis and remodeling have also been implicated in several diseases, such as diabetes, heart disease and Barth Syndrome. Although cardiolipin's structural and dynamic roles have been extensively studied in binary mixtures with other phospholipids, the biophysical properties of cardiolipin in ternary lipid mixtures are still not well resolved. Here, we used molecular dynamics simulations to investigate the cardiolipin-dependent properties of ternary lipid bilayer systems that mimic the major components of mitochondrial membranes. We found that changes to cardiolipin concentration only resulted in minor changes to bilayer structural features, but that the lipid diffusion was significantly affected by those alterations. We also found that cardiolipin position along the bilayer surfaces correlated to negative curvature deflections, consistent with the induction of negative curvature stress in the membrane monolayers. This work contributes to a foundational understanding of the role of CL in altering the properties in ternary lipid mixtures composed of the major mitochondrial phospholipids, providing much needed insights to help understand how cardiolipin concentration modulates the biophysical properties of mitochondrial membranes.

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Cardiolipin mediates membrane and channel interactions of the mitochondrial TIM23 protein import complex receptor Tim50

Abstract: Cardiolipin mediates dynamic receptor-channel interactions within the mitochondrial TIM23 protein import complex.

Cited by 52 publications

References 125 publications

Cardiolipin-Dependent Properties of Model Mitochondrial Membranes from Molecular Simulations

Cardiolipin-Dependent Properties of Model Mitochondrial Membranes from Molecular Simulations

Inner Mitochondrial Translocase Tim50 Is Central in Adrenal and Testicular Steroid Synthesis

Cardiolipin-Dependent Properties of Model Mitochondrial Membranes from Molecular Dynamics Simulations

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