Function-related asymmetry of the specific cardiolipin binding sites on the mitochondrial ADP/ATP carrier

Mao, Xiaoting; Yao, Shihao; Yi, Qiuzi; Xu, Zheming; Cang, Xiaohui

doi:10.1016/j.bbamem.2020.183466

Cited by 16 publications

(28 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cardiolipin (CL) is known to have a functional role, interacting with the protein moiety of the ADP/ATP mitochondrial transporter [45] . For this reason, the SLC25A29 sequence motifs corresponding to the cardiolipin binding sites in bANT1 [46] , [24] , [47] were identified from a sequence alignment ( Fig. 1 , Table S13) and used to analyse the interactions between CL molecules and SLC25A29 during the six MD simulations.…”

Section: Resultsmentioning

confidence: 99%

“…Numerous efforts have been made to describe and explain the functional role of the CL lipids in the inner mitochondrial membrane, and in particular with respect to the SLC25 transporter mechanism [24] , [46] , [47] . From the analyses of the MD simulations here performed, several contacts have been observed between CL molecules and the SLC25A29 protein.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Structural determinants of ligands recognition by the human mitochondrial basic amino acids transporter SLC25A29. Insights from molecular dynamics simulations of the c-state

Pasquadibisceglie

Polticelli

2021

Computational and Structural Biotechnology Journal

View full text Add to dashboard Cite

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Structural determinants of ligands recognition by the human mitochondrial basic amino acids transporter SLC25A29. Insights from molecular dynamics simulations of the c-state

Pasquadibisceglie

Polticelli

2021

Computational and Structural Biotechnology Journal

View full text Add to dashboard Cite

show abstract

“…Deficient CL models display perturbed TOM and TIM23 assembly, with resultant impaired protein import [10,95]. Moreover, a large body of evidence shows that CL stabilizes and preserves the activity of ADP/ATP carrier [9,96,97]. The stabilization and activity of other mitochondrial carriers, including phosphate carrier, pyruvate carrier, tricarboxylate carrier, the carnitine/acylcarnitine translocases, and calcium uniporter also require CL [98][99][100].…”

Section: Protein Importmentioning

confidence: 99%

Cardiolipin, Mitochondria, and Neurological Disease

Falabella

Vernon

Hanna

et al. 2021

Trends in Endocrinology & Metabolism

166

131

View full text Add to dashboard Cite

Over the past decade, it has become clear that lipid homeostasis is central to cellular metabolism. Lipids are particularly abundant in the central nervous system (CNS) where they modulate membrane fluidity, electric signal transduction, and synaptic stabilization. Abnormal lipid profiles reported in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and traumatic brain injury (TBI), are further support for the importance of lipid metablism in the nervous system. Cardiolipin (CL), a mitochondria-exclusive phospholipid, has recently emerged as a focus of neurodegenerative disease research. Aberrant CL content, structure, and localization are linked to impaired neurogenesis and neuronal dysfunction, contributing to aging and the pathogenesis of several neurodegenerative diseases, such as AD and PD. Furthermore, the highly tissue-specific acyl chain composition of CL confers it significant potential as a biomarker to diagnose and monitor the progression in several neurological diseases. CL also represents a potential target for pharmacological strategies aimed at treating neurodegeneration. Given the equipoise that currently exists between CL metabolism, mitochondrial function, and neurological disease, we review the role of CL in nervous system physiology and monogenic and neurodegenerative disease pathophysiology, in addition to its potential application as a biomarker and pharmacological target. Lipids and the Central Nervous SystemThe central nervous system (CNS) is rich in lipids, which account for approximately 50% of the total brain dry weight [1]. They are primarily localized to biological membranes, where they sustain CNS architecture and function. Sphingolipids, glycerophospholipids, and cholesterol are the predominant species and participate in a broad range of physiological functions, including cellular signaling (e.g., myelination to enable neuronal communication and nerve conduction, and lipid raft formation), energy balance, blood-brain barrier formation, and inflammatory responses [2]. It is therefore unsurprising that dysregulation of the CNS lipidome is associated with a broad spectrum of neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD) [2].Neuronal cellular functions have an extremely high metabolic rate, with the brain consuming up to 20% of the total body energy [2]. To fulfil this extensive energy requirement, neurons rely on glucose metabolism and mitochondrial oxidative phosphorylation (OXPHOS). Indeed, mitochondria function as sophisticated energy sensors that rapidly modulate their morphology and activity according to cellular energy demands. In addition to energy metabolism, mitochondria also participate in numerous biochemical and signaling pathways that are crucial for brain homeostasis, including cell death signaling, generation of free radical species, and lipid synthesis [3]. As a consequence of their bacterial ancestry, mitochondria have distinctive features that include multiple copies of a circular geno...

show abstract

“…Experimental studies have also been carried out that provide evidence of the activation of transmembrane proteins as a result of alterations to the lipid composition, e.g., using the mild detergent Triton X-100 [541,542], the relationship between lateral pressure profile and lipid composition was investigated both experimentally [697] and through MD simulation [698]. A few MD simulation studies found specific effects due to direct lipid interaction on protein behavior e.g., [699][700][701][702][703][704][705]; in most cases, the cholesterol molecules in the membrane were, however, most frequently shown to play the role of modulating the behavior of membrane proteins [706][707][708][709][710].…”

Section: Drug Membrane Interaction Can Play a Role In The Mechanism Of Drug Action-case Of Anestheticsmentioning

confidence: 99%

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

2021

View full text Add to dashboard Cite

We review the use of molecular dynamics (MD) simulation as a drug design tool in the context of the role that the lipid membrane can play in drug action, i.e., the interaction between candidate drug molecules and lipid membranes. In the standard “lock and key” paradigm, only the interaction between the drug and a specific active site of a specific protein is considered; the environment in which the drug acts is, from a biophysical perspective, far more complex than this. The possible mechanisms though which a drug can be designed to tinker with physiological processes are significantly broader than merely fitting to a single active site of a single protein. In this paper, we focus on the role of the lipid membrane, arguably the most important element outside the proteins themselves, as a case study. We discuss work that has been carried out, using MD simulation, concerning the transfection of drugs through membranes that act as biological barriers in the path of the drugs, the behavior of drug molecules within membranes, how their collective behavior can affect the structure and properties of the membrane and, finally, the role lipid membranes, to which the vast majority of drug target proteins are associated, can play in mediating the interaction between drug and target protein. This review paper is the second in a two-part series covering MD simulation as a tool in pharmaceutical research; both are designed as pedagogical review papers aimed at both pharmaceutical scientists interested in exploring how the tool of MD simulation can be applied to their research and computational scientists interested in exploring the possibility of a pharmaceutical context for their research.

show abstract

Function-related asymmetry of the specific cardiolipin binding sites on the mitochondrial ADP/ATP carrier

Cited by 16 publications

References 47 publications

Structural determinants of ligands recognition by the human mitochondrial basic amino acids transporter SLC25A29. Insights from molecular dynamics simulations of the c-state

Structural determinants of ligands recognition by the human mitochondrial basic amino acids transporter SLC25A29. Insights from molecular dynamics simulations of the c-state

Cardiolipin, Mitochondria, and Neurological Disease

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

Contact Info

Product

Resources

About