Perturbations in mitochondrial metabolism associated with defective cardiolipin biosynthesis: An in-organello real-time NMR study.

Mitochondria are central to cellular metabolism; hence, their dysfunction contributes to a wide array of human diseases. Cardiolipin, the signature phospholipid of the mitochondrion, affects proper cristae morphology, bioenergetic functions, and metabolic reactions carried out in mitochondrial membranes. To match tissue-specific metabolic demands, cardiolipin typically undergoes an acyl tail remodeling process with the final step carried out by the phospholipid-lysophospholipid transacylase tafazzin.

Perturbations in mitochondrial metabolism associated with defective cardiolipin biosynthesis: An real-time NMR study.

Mitochondria are central to cellular metabolism; hence, their dysfunction contributes to a wide array of human diseases including cancer, cardiopathy, neurodegeneration, and heritable pathologies such as Barth syndrome. Cardiolipin, the signature phospholipid of the mitochondrion promotes proper cristae morphology, bioenergetic functions, and directly affects metabolic reactions carried out in mitochondrial membranes. To match tissue-specific metabolic demands, cardiolipin typically undergoes an acyl tail remodeling process with the final step carried out by the phospholipid-lysophospholipid transacylase tafazzin.

Functional diversity among cardiolipin binding sites on the mitochondrial ADP/ATP carrier.

Lipid-protein interactions play a multitude of essential roles in membrane homeostasis. Mitochondrial membranes have a unique lipid-protein environment that ensures bioenergetic efficiency. Cardiolipin (CL), the signature mitochondrial lipid, plays multiple roles in promoting oxidative phosphorylation (OXPHOS).

Pain/Stress, Mitochondrial Dysfunction, and Neurodevelopment in Preterm Infants.

Introduction: Preterm infants experience tremendous early life pain/stress during their neonatal intensive care unit (NICU) hospitalization, which impacts their neurodevelopmental outcomes. Mitochondrial function/dysfunction may interface between perinatal stress events and neurodevelopment. Nevertheless, the specific proteins or pathways linking mitochondrial functions to pain-induced neurodevelopmental outcomes in infants remain unidentified.

Interactions of amyloidogenic proteins with mitochondrial protein import machinery in aging-related neurodegenerative diseases.

Most mitochondrial proteins are targeted to the organelle by N-terminal mitochondrial targeting sequences (MTSs, or "presequences") that are recognized by the import machinery and subsequently cleaved to yield the mature protein. MTSs do not have conserved amino acid compositions, but share common physicochemical properties, including the ability to form amphipathic α-helical structures enriched with basic and hydrophobic residues on alternating faces. The lack of strict sequence conservation implies that some polypeptides can be mistargeted to mitochondria, especially under cellular stress.

Peptide Power: Mechanistic Insights into the Effect of Mitochondria-Targeted Tetrapeptides on Membrane Electrostatics from Molecular Simulations.

Mitochondrial dysfunction is implicated in nine of the ten leading causes of death in the US, yet there are no FDA-approved therapeutics to treat it. Synthetic mitochondria-targeted peptides (MTPs), including the lead compound SS-31, offer promise, as they have been shown to restore healthy mitochondrial function and treat a variety of common diseases. At the cellular level, research has shown that MTPs accumulate strongly at the inner mitochondrial membrane (IMM), slow energy sinks (e.

Using Live Cell STED Imaging to Visualize Mitochondrial Inner Membrane Ultrastructure in Neuronal Cell Models.

Mitochondria play many essential roles in the cell, including energy production, regulation of Ca homeostasis, lipid biosynthesis, and production of reactive oxygen species (ROS). These mitochondria-mediated processes take on specialized roles in neurons, coordinating aerobic metabolism to meet the high energy demands of these cells, modulating Ca signaling, providing lipids for axon growth and regeneration, and tuning ROS production for neuronal development and function. Mitochondrial dysfunction is therefore a central driver in neurodegenerative diseases.

Conserved cardiolipin-mitochondrial ADP/ATP carrier interactions assume distinct structural and functional roles that are clinically relevant.

The mitochondrial phospholipid cardiolipin (CL) promotes bioenergetics via oxidative phosphorylation (OXPHOS). Three tightly bound CLs are evolutionarily conserved in the ADP/ATP carrier (AAC in yeast; adenine nucleotide translocator, ANT in mammals) which resides in the inner mitochondrial membrane and exchanges ADP and ATP to enable OXPHOS. Here, we investigated the role of these buried CLs in the carrier using yeast Aac2 as a model.

Interhemispheric transfer time and concussion in adolescents: A longitudinal study using response time and event-related potential measures.

Introduction: Concussion in children and adolescents is a public health concern with higher concussion incidence than adults and increased susceptibility to axonal injury. The corpus callosum is a vulnerable location of concussion-related white matter damage that can be associated with short- and long-term effects of concussion. Interhemispheric transfer time (IHTT) of visual information across the corpus callosum can be used as a direct measure of corpus callosum functioning that may be impacted by adolescent concussion with slower IHTT relative to matched controls.

Associations of Mitochondrial Function, Stress, and Neurodevelopmental Outcomes in Early Life: A Systematic Review.

Early life stress is commonly experienced by infants, especially preterm infants, and may impact their neurodevelopmental outcomes in their early and later lives. Mitochondrial function/dysfunction may play an important role underlying the linkage of prenatal and postnatal stress and neurodevelopmental outcomes in infants. This review aimed to provide insights on the relationship between early life stress and neurodevelopment and the mechanisms of mitochondrial function/dysfunction that contribute to the neuropathology of stress.

Structure-activity relationships of mitochondria-targeted tetrapeptide pharmacological compounds.

Mitochondria play a central role in metabolic homeostasis, and dysfunction of this organelle underpins the etiology of many heritable and aging-related diseases. Tetrapeptides with alternating cationic and aromatic residues such as SS-31 (elamipretide) show promise as therapeutic compounds for mitochondrial disorders. In this study, we conducted a quantitative structure-activity analysis of three alternative tetrapeptide analogs, benchmarked against SS-31, that differ with respect to aromatic side chain composition and sequence register.

Mitochondrial compartmentalization: emerging themes in structure and function.

Within cellular structures, compartmentalization is the concept of spatial segregation of macromolecules, metabolites, and biochemical pathways. Therefore, this concept bridges organellar structure and function. Mitochondria are morphologically complex, partitioned into several subcompartments by a topologically elaborate two-membrane system.

Reduction of elevated proton leak rejuvenates mitochondria in the aged cardiomyocyte.

Aging-associated diseases, including cardiac dysfunction, are increasingly common in the population. However, the mechanisms of physiologic aging in general, and cardiac aging in particular, remain poorly understood. Age-related heart impairment is lacking a clinically effective treatment.

Baseline Gonadotropin Levels and Testosterone Response in Hypogonadal Men Treated With Clomiphene Citrate.

Objective: To investigate the role of baseline gonadotropins in predicting the biochemical response to clomiphene citrate (CC) treatment.

Methods: We conducted a retrospective review of data from hypogonadal men treated with CC in 2 high-volume fertility centers between 2013 and 2018. Patient age, body mass index, and baseline hormones (follicle stimulating hormone [FSH], luteinizing hormone [LH], and total testosterone [TT]) were obtained.

The mitochondria-targeted peptide SS-31 binds lipid bilayers and modulates surface electrostatics as a key component of its mechanism of action.

Mitochondrial dysfunction underlies many heritable diseases, acquired pathologies, and aging-related declines in health. Szeto-Schiller (SS) peptides comprise a class of amphipathic tetrapeptides that are efficacious toward a wide array of mitochondrial disorders and are believed to target mitochondrial membranes because they are enriched in the anionic phospholipid cardiolipin (CL). However, little is known regarding how SS peptides interact with or alter the physical properties of lipid bilayers.

Obesity and Baseline Estradiol Levels Are Independent Predictors for Initiation of Anastrozole in Hypogonadal Men on Clomiphene Citrate.

Purpose: To assess the conversion rate from clomiphene citrate (CC) monotherapy to combination CC+anastrozole (AZ) therapy in hypogonadal men and the predictors associated with the initiation of AZ.

Materials And Methods: A retrospective review of records from hypogonadal men treated with CC in a single fertility center was performed from 2013 to 2018. Patient age, body mass index (BMI), blood pressure, and reproductive hormones were obtained at baseline.

Astaxanthin attenuates the increase in mitochondrial respiration during the activation of hepatic stellate cells.

Upon liver injury, quiescent hepatic stellate cells (qHSCs) transdifferentiate to myofibroblast-like activated HSCs (aHSCs), which are primarily responsible for the accumulation of extracellular matrix proteins during the development of liver fibrosis. Therefore, aHSCs may exhibit different energy metabolism from that of qHSCs to meet their high energy demand. We previously demonstrated that astaxanthin (ASTX), a xanthophyll carotenoid, prevents the activation of HSCs.

Phosphatidylethanolamine made in the inner mitochondrial membrane is essential for yeast cytochrome bc complex function.

Of the four separate PE biosynthetic pathways in eukaryotes, one occurs in the mitochondrial inner membrane (IM) and is executed by phosphatidylserine decarboxylase (Psd1). Deletion of Psd1 is lethal in mice and compromises mitochondrial function. We hypothesize that this reflects inefficient import of non-mitochondrial PE into the IM.

Combination therapy with clomiphene citrate and anastrozole is a safe and effective alternative for hypoandrogenic subfertile men.

Objectives: To assess the efficacy and safety of combination therapy with clomiphene citrate (CC) and anastrozole (AZ) for male hypoandrogenism.

Patients And Methods: We identified patients treated with a combination of CC + AZ in the period 2014 to 2017. Data were gathered on patient characteristics and laboratory values at baseline.

Molecular Dynamics Analysis of Cardiolipin and Monolysocardiolipin on Bilayer Properties.

The mitochondrial lipid cardiolipin (CL) contributes to the spatial protein organization and morphological character of the inner mitochondrial membrane. Monolysocardiolipin (MLCL), an intermediate species in the CL remodeling pathway, is enriched in the multisystem disease Barth syndrome. Despite the medical relevance of MLCL, a detailed molecular description that elucidates the structural and dynamic differences between CL and MLCL has not been conducted.

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

The phospholipid cardiolipin mediates the functional interactions of proteins that reside within energy-conserving biological membranes. However, the molecular basis by which this lipid performs this essential cellular role is not well understood. We address this role of cardiolipin using the multisubunit mitochondrial TIM23 protein transport complex as a model system.