Pharmacological inhibition of ALCAT1 mitigates amyotrophic lateral sclerosis by attenuating SOD1 protein aggregation

Li, Xueling; Zhang, Jun; Li, Jie; Song, Chengjie; Shi, Yuguang

doi:10.1016/j.molmet.2022.101536

Cited by 9 publications

(4 citation statements)

References 65 publications

(127 reference statements)

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“…Inducible deletion of PTPMT1 in cerebella only causes a transient defect in adult mice that soon recover and appear grossly normal afterward [ 105 ], indicating that CL might play a less important role in the maintenance of brain functioning than in brain development. Intriguingly, the ablation of ALCAT1 activity in mice could either attenuate motor neuron dysfunction, inflammation, and muscle atrophy in a model of ALS [ 122 ], or inhibit MPTP-induced neurotoxicity, apoptosis, and motor deficits [ 40 ], indicating that ALCAT1 may be a therapeutic target for treating neuronal diseases. Regardless, the role of CL in neurons is not fully understood, and more studies should be performed in the future to investigate the effects of CL deficiency in different types of neurons and in distinct neurological disease models.…”

Section: CL In Neuronal Diseasesmentioning

confidence: 99%

Cardiolipin Regulates Mitochondrial Ultrastructure and Function in Mammalian Cells

Jiang

Shen

Huynh

et al. 2022

Genes

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Cardiolipin (CL) is a unique, tetra-acylated diphosphatidylglycerol lipid that mainly localizes in the inner mitochondria membrane (IMM) in mammalian cells and plays a central role in regulating mitochondrial architecture and functioning. A deficiency of CL biosynthesis and remodeling perturbs mitochondrial functioning and ultrastructure. Clinical and experimental studies on human patients and animal models have also provided compelling evidence that an abnormal CL content, acyl chain composition, localization, and level of oxidation may be directly linked to multiple diseases, including cardiomyopathy, neuronal dysfunction, immune cell defects, and metabolic disorders. The central role of CL in regulating the pathogenesis and progression of these diseases has attracted increasing attention in recent years. In this review, we focus on the advances in our understanding of the physiological roles of CL biosynthesis and remodeling from human patients and mouse models, and we provide an overview of the potential mechanism by which CL regulates the mitochondrial architecture and functioning.

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Section: CL In Neuronal Diseasesmentioning

confidence: 99%

Cardiolipin Regulates Mitochondrial Ultrastructure and Function in Mammalian Cells

Jiang

Shen

Huynh

et al. 2022

Genes

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“…Our findings demonstrate that CMP3013 exhibits strong binding affinity to artificial IMMs that mimic the effects of pathogenic CL remodeling, including membranes containing 10% DLCL or reduced CL levels (from 20 to 5%) (Figure ). These results indicate that CMP3013 can rescue mitochondrial dysfunction resulting from CL peroxidation or remodeling, surpassing the limitations of gene expression attenuation . Moreover, these findings highlight the capability of CMP3013 to inhibit pathological CL remodeling in the IMM at nanomolar concentrations, an effect that cannot be accomplished by other known molecules.…”

Section: Discussionmentioning

confidence: 92%

“…These results indicate that CMP3013 can rescue mitochondrial dysfunction resulting from CL peroxidation or remodeling, surpassing the limitations of gene expression attenuation. 47 Moreover, these findings highlight the capability of CMP3013 to inhibit pathological CL remodeling in the IMM at nanomolar concentrations, an effect that cannot be accomplished by other known molecules.…”

Section: Discussionmentioning

confidence: 99%

Cyclohexylalanine-Containing α-Helical Amphipathic Peptide Targets Cardiolipin, Rescuing Mitochondrial Dysfunction in Kidney Injury

Shin,

Hyun,

Kim

et al. 2023

J. Med. Chem.

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Mitochondrial dysfunction is linked to degenerative diseases, resulting from cardiolipin (CL)-induced disruption of cristae structure in the inner mitochondrial membrane (IMM); therefore, preserving cristae and preventing CL remodeling offer effective strategies to maintain mitochondrial function. To identify reactive oxygen species (ROS)-blocking agents against mitochondrial dysfunction, a library of cyclohexylamine-containing cell-penetrating αhelical amphipathic "bundle" peptides were screened. Among these, CMP3013 is selectively bound to abnormal mitochondria, preserving the cristae structure impaired by mitochondriadamaging agents. With a stronger affinity for CL compared with other IMM lipid components, CMP3013 exhibited high selectivity. Consequently, it protected cristae, reduced ROS production, and enhanced adenosine triphosphate (ATP) generation. In mouse models of acute kidney injury, a 1 mg/kg dose of CMP3013 demonstrated remarkable efficacy, highlighting its potential as a therapeutic agent for mitochondrial dysfunction-related disorders. Overall, CMP3013 represents a promising agent for mitigating mitochondrial dysfunction and associated diseases.

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“…However, copper can cause hydromineral regulatory malfunction, stressing or killing organisms, when the copper concentrations exceed the nutritional needs [4]. Disruptions in the homeostatic mechanisms of copper metabolism in brain are associated with human neurodegenerative disorders such as Menkes disease, Wilson's disease, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis [5,6]. In addition, copper displayed adverse effects on various aquatic organisms, including fish, algae, Daphnia, etc.…”

Section: Introductionmentioning

confidence: 99%

Toxic Effects of Copper Fungicides on the Development and Behavior of Zebrafish in Early-Life Stages

Gao,

Yuan,

Zhang

et al. 2023

Nanomaterials

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Copper-based fungicides have been used to control various plant diseases for more than one hundred years and play very important roles in agriculture. Accumulation of copper in freshwater and environment pose severe threats to human health and the environment. The current study evaluated the developmental and behavioral toxicity of PEG@Cu NCs (copper nanoclusters), Kocide® 3000 (copper hydroxide), and Cu(CH3COO)2 (copper acetate) to zebrafish in early-life stages. The developmental toxicity was evaluated according to the parameters of mortality, hatching rate, autonomous movement and heartbeat of embryos, and body length of larvae. The 9 dpf (days postfertilization)-LC50 (50% lethal concentration) of embryonic mortality was 0.077, 0.174 or 0.088 mg/L, and the 9 dpf-EC50 (effective concentration of 50% embryos hatching) of hatching rate was 0.079 mg/L, 0.21 mg/L and 0.092 mg/L when the embryos were exposed to PEG@Cu NCs, Kocide® 3000 or Cu(CH3COO)2, respectively. Kocide® 3000 and Cu(CH3COO)2 obviously decreased the spontaneous movements, while PEG@Cu NCs had no adverse effects on that of embryos. The reduced heartbeat can return to normal after exposure to PEG@Cu NCs for 96 h, while it cannot recover from Kocide® 3000. In addition, Kocide® 3000 (≥0.2 mg/L), PEG@Cu NCs and Cu(CH3COO)2 with 0.05 mg/L or higher concentration exhibited obvious behavioral toxicity to zebrafish larvae according to the parameters of movement distance, average velocity, absolute sinuosity, absolute turn angle and absolute angular velocity.

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Pharmacological inhibition of ALCAT1 mitigates amyotrophic lateral sclerosis by attenuating SOD1 protein aggregation

Cited by 9 publications

References 65 publications

Cardiolipin Regulates Mitochondrial Ultrastructure and Function in Mammalian Cells

Cardiolipin Regulates Mitochondrial Ultrastructure and Function in Mammalian Cells

Cyclohexylalanine-Containing α-Helical Amphipathic Peptide Targets Cardiolipin, Rescuing Mitochondrial Dysfunction in Kidney Injury

Toxic Effects of Copper Fungicides on the Development and Behavior of Zebrafish in Early-Life Stages

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