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Cardiolipin is important for cristae structure and supercomplex formation on the inner mitochondrial membrane (IMM). The protein complexes of the electron transport chain reside on cristae membranes and cardiolipin (CL) provides curvatures on the IMM to increase surface area for the respiratory complexes. Cardiolipin also helps to organize the respiratory complexes into supercomplexes to facilitate electron transfer among the redox partners. Lastly, cardiolipin anchors the highly cationic cyt c (C) via electrostatic interaction to bring it in close proximity to Complex III and Complex IV for efficient electron transfer. IMS: intermembrane space.
Source publication
A decline in energy is common in aging, and the restoration of mitochondrial bioenergetics may offer a common approach for the treatment of numerous age‐associated diseases. Cardiolipin is a unique phospholipid that is exclusively expressed on the inner mitochondrial membrane where it plays an important structural role in cristae formation and the...
Citations
... 5 This mitochondria-targeting peptide binds to cardiolipin, resulting in improved membrane stability, enhanced adenosine triphosphate (ATP) production, and reduced production of pathogenic reactive oxygen species (ROS) (Figure 1). [5][6][7] In this case report, we present the use of elamipretide under an expanded access program (EAP) in a patient with MPAN, with the goal of providing support for this agent's therapeutic role in patients with rare neuromuscular disorders, such as MPAN. ...
... Supportive care for MPAN patients includes pharmacologic treatment of spasticity, dystonia, and parkinsonism (e.g., trihexyphenidyl, baclofen, and intramuscular botulinum toxin injections); psychiatric treatment of neuropsychiatric manifestations; occupational, physical, and speech therapies; nutritional supplements and gastric tube feeding; and management of secretions and aspiration risk (e.g., scopolamine patch, glycopyrrolate, and/or tracheostomy). 1 The therapeutic effect of iron chelation with deferiprone has not been proven in MPAN patients, showing mixed results in the few published case reports. 19,20 Elamipretide is a mitochondria-targeting agent that has offered promise in patients with degenerative neuromuscular disorders, such as PMM. 4 Through its association with cardiolipin, elamipretide improves mitochondrial function through improvement in ATP production and potential reversal of damaging oxidative stress, 6,7 issues which may be associated with pathogenic variants in C19orf12. 15 Our case is the first to use elamipretide in the treatment of a patient with MPAN. ...
Key Clinical Message
This case report presents a progressively declining 17‐year‐old patient with membrane protein‐associated neurodegeneration who demonstrated symptomatic improvements in her dysarthria, dysphagia, and gait, and objective improvements in her 6‐minute walk test and 5 times sit‐to‐stand test during elamipretide treatment.
... SS-31, also known as Elamipretide, a cell-permeable peptide, selectively targets the inner mitochondrial membrane via cardiolipin binding, thereby reducing mitochondrial ROS production and restoring mitochondrial bioenergetics [87]. It stabilizes cardiolipin, promotes membrane restructuring, and facilitates the formation of mitochondrial supercomplexes, thereby reducing ROS production [87][88][89][90]. Recent studies have focused on mitochondrial targets such as elamipretide and NAD+ supplementation. ...
... Elamipretide/SS-31 [87][88][89][90] It concentrates on mitochondrial membranes and helps regulate energy production by enhancing the efficiency of the electron transport chain. Additionally, Elamipretide can reduce oxidative stress, stabilize mitochondrial membranes, and preserve mitochondrial integrity. ...
Hypertrophic cardiomyopathy (HCM) is a heart condition characterized by cellular and metabolic dysfunction, with mitochondrial dysfunction playing a crucial role. Although the direct relationship between genetic mutations and mitochondrial dysfunction remains unclear, targeting mitochondrial dysfunction presents promising opportunities for treatment, as there are currently no effective treatments available for HCM. This review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Reviews guidelines. Searches were conducted in databases such as PubMed, Embase, and Scopus up to September 2023 using "MESH terms". Bibliographic references from pertinent articles were also included. Hypertrophic cardiomy-opathy (HCM) is influenced by ionic homeostasis, cardiac tissue remodeling, metabolic balance, genetic mutations, reactive oxygen species regulation, and mitochondrial dysfunction. The latter is a common factor regardless of the cause and is linked to intracellular calcium handling, energetic and oxidative stress, and HCM-induced hypertrophy. Hypertrophic cardiomyopathy treatments focus on symptom management and complication prevention. Targeted therapeutic approaches, such as improving mitochondrial bioenergetics, are being explored. This includes coenzyme Q and elamipretide therapies and metabolic strategies like therapeutic ketosis. Understanding the biomolecular, genetic, and mitochondrial mechanisms underlying HCM is crucial for developing new therapeutic modalities.
... Elevated S100A8/A9 levels drive the post-AMI progression of the inflammatory response and mitochondrial dysfunction. Several anti-inflammatory agents or mitochondria-targeting peptides are promising drugs for cardiovascular disease 31,32 , and these treatments may be more effective for patients with high S100A8/A9 levels. S100A8/A9 levels are elevated before overt HF, and S100A9 blockade reportedly improves cardiac function in experimental MI and ischemia-reperfusion 14,20,21 . ...
Heart failure is the prevalent complication of acute myocardial infarction. We aim to identify a biomarker for heart failure post-acute myocardial infarction. This observational study includes 1062 and 1043 patients with acute myocardial infarction in the discovery and validation cohorts, respectively. The outcomes are in-hospital and long-term heart failure events. S100A8/A9 is screened out through proteomic analysis, and elevated circulating S100A8/A9 is independently associated with heart failure in discovery and validation cohorts. Furthermore, the predictive value of S100A8/A9 is superior to the traditional biomarkers, and the addition of S100A8/A9 improves the risk estimation using traditional risk factors. We finally report causal effect of S100A8/A9 on heart failure in three independent cohorts using Mendelian randomization approach. Here, we show that S100A8/A9 is a predictor and potentially causal medicator for heart failure post-acute myocardial infarction.
... Aβ and pTau-induced oxidative damage inhibits mitophagy [71]. Moreover, Aβ and pTau determine the enlargement of mPTP causing the decrease of the intermembrane potential [72], the leakage of cytochrome C and, thus, the triggering of apoptosis [73]. Both mitochondrial dynamics and biogenesis are impaired in AD where decreased expression of PGC-1α, TFAM and GABP proteins are observed [74,75]. ...
Carnosic acid (CA), a diterpene obtained mainly from Rosmarinus officinalis and Salvia officinalis, exerts antioxidant, anti-inflammatory, and anti-apoptotic effects in mammalian cells. At least in part, those benefits are associated with the ability that CA modulates mitochondrial physiology. CA attenuated bioenergetics collapse and redox impairments in the mitochondria obtained from brain cells exposed to several toxicants in both in vitro and in vivo experimental models. CA is a potent inducer of the major modulator of the redox biology in animal cells, the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which controls the expression of a myriad of genes whose products are involved with cytoprotection in different contexts. Moreover, CA upregulates signaling pathways related to the degradation of damaged mitochondria (mitophagy) and with the synthesis of these organelles (mitochondrial biogenesis). Thus, CA may be considered an agent that induces mitochondrial renewal, depending on the circumstances. In this review, we discuss about the mechanisms of action by which CA promotes mitochondrial protection in brain cells.
... SS-31 has a wide range of applications in the treatment of various diseases, especially in the protection of cardiolipin from OS attack, which effectively protects cardiac function and simplifies the treatment of diseases with complex pathologies. Among the cardiolipinprotecting agents, it is the "first-in-class" one [150]. Table 2 summarizes the application of antioxidant peptides in treating diseases, especially SS-31, which is widely used. ...
Antioxidant peptides are currently a hotspot in food science, pharmaceuticals, and cosmetics. In different fields, the screening, activity evaluation, mechanisms, and applications of antioxidant peptides are the pivotal areas of research. Among these topics, the efficient screening of antioxidant peptides stands at the forefront of cutting-edge research. To this end, efficient screening with novel technologies has significantly accelerated the research process, gradually replacing the traditional approach. After the novel antioxidant peptides are screened and identified, a time-consuming activity evaluation is another indispensable procedure, especially in in vivo models. Cellular and rodent models have been widely used for activity evaluation, whilst non-rodent models provide an efficient solution, even with the potential for high-throughput screening. Meanwhile, further research of molecular mechanisms can elucidate the essence underlying the activity, which is related to several signaling pathways, including Keap1-Nrf2/ARE, mitochondria-dependent apoptosis, TGF-β/SMAD, AMPK/SIRT1/PGC-1α, PI3K/Akt/mTOR, and NF-κB. Last but not least, antioxidant peptides have broad applications in food manufacture, therapy, and the cosmetics industry, which requires a systematic review. This review introduces novel technologies for the efficient screening of antioxidant peptides, categorized with a new vision. A wide range of activity evaluation assays, encompassing cellular models, as well as rodent and non-rodent models, are provided in a comprehensive manner. In addition, recent advances in molecular mechanisms are analyzed with specific cases. Finally, the applications of antioxidant peptides in food production, therapy, and cosmetics are systematically reviewed.
... Elamipretide binds to and stabilizes cardiolipin, a phospholipid crucial for the optimal assembly and functioning of the mitochondrial respiratory chain. Consequently, this interaction leads to a reduction in mitochondrial ROS production, enhancement of oxidative phosphorylation, and augmentation of ATP production [182,183]. ...
Purpose of Review
This review explores the interplay among metabolic dysfunction, oxidative stress, inflammation, and fibrosis in Fabry disease, focusing on their potential implications for cardiac involvement. We aim to discuss the biochemical processes that operate in parallel to sphingolipid accumulation and contribute to disease pathogenesis, emphasizing the importance of a comprehensive understanding of these processes.
Recent Findings
Beyond sphingolipid accumulation, emerging studies have revealed that mitochondrial dysfunction, oxidative stress, and chronic inflammation could be significant contributors to Fabry disease and cardiac involvement. These factors promote cardiac remodeling and fibrosis and may predispose Fabry patients to conduction disturbances, ventricular arrhythmias, and heart failure. While current treatments, such as enzyme replacement therapy and pharmacological chaperones, address disease progression and symptoms, their effectiveness is limited.
Summary
Our review uncovers the potential relationships among metabolic disturbances, oxidative stress, inflammation, and fibrosis in Fabry disease–related cardiac complications. Current findings suggest that beyond sphingolipid accumulation, other mechanisms may significantly contribute to disease pathogenesis. This prompts the exploration of innovative therapeutic strategies and underscores the importance of a holistic approach to understanding and managing Fabry disease.
... This pharmaceutical preparation has been used for the treatment of gout and hyperuricemia, but also in type 2 diabetes [111]. SS-31 (Elamipretide, Bendavia, MTP-131) is a pharmaceutical preparation used to stabilize cardiolipin from the mitochondrial membrane; thus, the excessive production of ROS is prevented [112]. This pharmaceutical preparation has been used for the treatment of gout and hyperuricemia, but also in heart failure [113]. ...
This review aimed at searching literature for data regarding the inflammasomes’ involvement in the pathogenesis of oral diseases (mainly periodontitis) and general pathologies, including approaches to control inflammasome-related pathogenic mechanisms. The inflammasomes are part of the innate immune response that activates inflammatory caspases by canonical and noncanonical pathways, to control the activity of Gasdermin D. Once an inflammasome is activated, pro-inflammatory cytokines, such as interleukins, are released. Thus, inflammasomes are involved in inflammatory, autoimmune and autoinflammatory diseases. The review also investigated novel therapies based on the use of phytochemicals and pharmaceutical substances for inhibiting inflammasome activity. Pharmaceutical substances can control the inflammasomes by three mechanisms: inhibiting the intracellular signaling pathways (Allopurinol and SS-31), blocking inflammasome components (VX-765, Emricasan and VX-740), and inhibiting cytokines mediated by the inflammasomes (Canakinumab, Anakinra and Rilonacept). Moreover, phytochemicals inhibit the inflammasomes by neutralizing reactive oxygen species. Biomaterials functionalized by the adsorption of therapeutic agents onto different nanomaterials could represent future research directions to facilitate multimodal and sequential treatment in oral pathologies.
... To further determine how ROS-mediated mitochondrial dysfunction underlies CaT alternans, we tested the effects of SS-31, a Szeto-Schiller peptide that has been shown to improve mitochondrial function impaired by oxidative stress [74,75]. Mitochondrial O 2 ·− overproduction plays a key role in the development of heart diseases such as MI, hypertensive cardiomyopathy, IR-injury and HF where SS-31 treatment has improved mitochondrial function, cardiac remodeling and left ventricular function, and has decreased mortality [12,15,38,76,77]. ...
... SS-31 binds by electrostatic and hydrophobic interactions selectively to cardiolipin (CL), a phospholipid that exclusively resides in the internal mitochondrial membrane. CL is a platform for electrostatic interaction with cyt c to facilitate the electron transfer between Complex III and IV, and CL plays a key role in stabilizing cristae architecture and the stabilization of respiratory complexes into supercomplexes [74,78]. Although the mechanisms are not completely understood, in the presence of H 2 O 2 cyt c can undergo a CL-mediated conformational change that promotes its conversion from an electron carrier into a peroxidase/oxygenase. ...
Atrial calcium transient (CaT) alternans is defined as beat-to-beat alternations in CaT amplitude and is causally linked to atrial fibrillation (AF). Mitochondria play a significant role in cardiac excitation–contraction coupling and Ca signaling through redox environment regulation. In isolated rabbit atrial myocytes, ROS production is enhanced during CaT alternans, measured by fluorescence microscopy. Exogenous ROS (tert-butyl hydroperoxide) enhanced CaT alternans, whereas ROS scavengers (dithiothreitol, MnTBAP, quercetin, tempol) alleviated CaT alternans. While the inhibition of cellular NADPH oxidases had no effect on CaT alternans, interference with mitochondrial ROS (ROSm) production had profound effects: (1) the superoxide dismutase mimetic MitoTempo diminished CaT alternans and shifted the pacing threshold to higher frequencies; (2) the inhibition of cyt c peroxidase by SS-31, and inhibitors of ROSm production by complexes of the electron transport chain S1QEL1.1 and S3QEL2, decreased the severity of CaT alternans; however (3) the impairment of mitochondrial antioxidant defense by the inhibition of nicotinamide nucleotide transhydrogenase with NBD-Cl and thioredoxin reductase-2 with auranofin enhanced CaT alternans. Our results suggest that intact mitochondrial antioxidant defense provides crucial protection against pro-arrhythmic CaT alternans. Thus, modulating the mitochondrial redox state represents a potential therapeutic approach for alternans-associated arrhythmias, including AF.
... The IMM is folded into cristae, to increase the surface area available for oxidative phosphorylation 106 . During aging, organization of these cristae is disrupted 107,108 and the activity of the ETC is decreased 106,109 . Both are a result of changing phospholipid content of the IMM and the resulting decreased membrane fluidity. ...
... Cardiolipin, a phospholipid exclusive to the IMM, is a likely candidate. Its conical structure enables the membrane to form curves 109 . Cardiolipin content decreases with age and experimental addition of it to aged mitochondria increased function 109,110 . ...
... Its conical structure enables the membrane to form curves 109 . Cardiolipin content decreases with age and experimental addition of it to aged mitochondria increased function 109,110 . Doxorubicin accumulates in mitochondria, partially by binding to cardiolipin 111,112 . ...
The population of cancer survivors is rapidly increasing due to improving healthcare. However, cancer therapies often have long-term side effects. One example is cancer therapy-related cardiac dysfunction (CTRCD) caused by doxorubicin: up to 9% of the cancer patients treated with this drug develop heart failure at a later stage. In recent years, doxorubicin-induced cardiotoxicity has been associated with an accelerated aging phenotype and cellular senescence in the heart. In this review we explain the evidence of an accelerated aging phenotype in the doxorubicin-treated heart by comparing it to healthy aged hearts, and shed light on treatment strategies that are proposed in pre-clinical settings. We will discuss the accelerated aging phenotype and the impact it could have in the clinic and future research.
... Interestingly, it was suggested that a small mitochondriatargeted tetrapeptide, Elamipretide/MTP-131, is able to ameliorate mitochondrial dysfunction in different model systems of a range of diseases, including PD and neurodegeneration [92,93]. This tetrapeptide can cross the blood-brain barrier [94,95], entering neural cells, where it is absorbed by mitochondria and binds to the inner mitochondrial membrane phospholipid cardiolipin [96,97]. The neuroprotective effects of Elamipretide are mediated by inhibition of neural oxidative stress, neuroinflammation, toxic protein accumulation, and neural apoptosis [93]. ...
Background
Loss-of-function mutations in the PRKN gene, encoding Parkin, are the most common cause of autosomal recessive Parkinson’s disease (PD). We have previously identified mitoch
ondrial Stomatin-like protein 2 (SLP-2), which functions in the assembly of respiratory chain proteins, as a Parkin-binding protein. Selective knockdown of either Parkin or SLP-2 led to reduced mitochondrial and neuronal function in neuronal cells and Drosophila, where a double knockdown led to a further worsening of Parkin-deficiency phenotypes. Here, we investigated the minimal Parkin region involved in the Parkin-SLP-2 interaction and explored the ability of Parkin-fragments and peptides from this minimal region to restore mitochondrial function.
Methods
In fibroblasts, human induced pluripotent stem cell (hiPSC)-derived neurons, and neuroblastoma cells the interaction between Parkin and SLP-2 was investigated, and the Parkin domain responsible for the binding to SLP-2 was mapped. High resolution respirometry, immunofluorescence analysis and live imaging were used to analyze mitochondrial function.
Results
Using a proximity ligation assay, we quantitatively assessed the Parkin-SLP-2 interaction in skin fibroblasts and hiPSC-derived neurons. When PD-associated PRKN mutations were present, we detected a significantly reduced interaction between the two proteins. We found a preferential binding of SLP-2 to the N-terminal part of Parkin, with a highest affinity for the RING0 domain. Computational modeling based on the crystal structure of Parkin protein predicted several potential binding sites for SLP-2 within the Parkin RING0 domain. Amongst these, three binding sites were observed to overlap with natural PD-causing missense mutations, which we demonstrated interfere substantially with the binding of Parkin to SLP-2. Finally, delivery of the isolated Parkin RING0 domain and a Parkin mini-peptide, conjugated to cell-permeant and mitochondrial transporters, rescued compromised mitochondrial function in Parkin-deficient neuroblastoma cells and hiPSC-derived neurons with endogenous, disease causing PRKN mutations.
Conclusions
These findings place further emphasis on the importance of the protein–protein interaction between Parkin and SLP-2 for the maintenance of optimal mitochondrial function. The possibility of restoring an abolished binding to SLP-2 by delivering the Parkin RING0 domain or the Parkin mini-peptide involved in this specific protein–protein interaction into cells might represent a novel organelle-specific therapeutic approach for correcting mitochondrial dysfunction in Parkin-linked PD.
