A fragment of adhesion molecule L1 is imported into mitochondria, and regulates mitochondrial metabolism and trafficking

Kraus, Kristina; Kleene, Ralf; Braren, Ingke; Loers, Gabriele; Lutz, David; Schachner, Melitta

doi:10.1242/jcs.210500

Cited by 19 publications

(42 citation statements)

References 56 publications

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“…In the present study, PS and TC prevented the impairment of mitochondrial function and the reduction in the ATP levels. This beneficial function of PS and TC is supported by previous observations on the beneficial action of an L1 fragment, which is imported into mitochondria, where it interacts with the complex I subunit NDUFV2 (Kraus et al, 2018).…”

Section: Discussionsupporting

confidence: 75%

Adhesion Molecule L1 Agonist Mimetics Protect Against the Pesticide Paraquat-Induced Locomotor Deficits and Biochemical Alterations in Zebrafish

et al. 2020

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Besides several endogenous elements, exogenous factors, including exposure to pesticides, have been recognized as putative factors contributing to the onset and development of neurodegenerative diseases, including Parkinson's disease (PD). Considering the availability, success rate, and limitations associated with the current arsenals to fight PD, there is an unmet need for novel therapeutic interventions. Therefore, based on the previously reported beneficial functions of the L1 cell adhesion molecule, we hypothesized that L1 mimetic compounds may serve to neutralize neurotoxicity triggered by the pesticide paraquat (PQ). In this study, we attempt to use PQ for inducing PD-like pathology and the L1 mimetic compounds phenelzine sulfate (PS) and tacrine (TC) as potential candidates for the amelioration of PD symptoms using zebrafish as a model system. Administration of PQ together with the L1 mimetic compounds PS or TC (250 nM) improved survival of zebrafish larvae, protected them from locomotor deficits, and increased their sensorimotor reflexes. Moreover, application of PQ together with PS (500 nM) or TC (1000 nM) in adult zebrafish counteracted PQ-induced toxicity, maintaining normal locomotor functions and spatial memory in an open field and T-maze task, respectively. Both L1 mimetic compounds prevented reduction in tyrosine hydroxylase and dopamine levels, reduced reactive oxygen species (ROS) generation, protected against impairment of mitochondrial viability, improved the antioxidant enzyme system, and prevented a decrease in ATP levels. Altogether, our findings highlight the beneficial functions of the agonistic L1 mimetics PS and TC by improving several vital cell functions against PQ-triggered neurotoxicity.

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Section: Discussionsupporting

confidence: 75%

Adhesion Molecule L1 Agonist Mimetics Protect Against the Pesticide Paraquat-Induced Locomotor Deficits and Biochemical Alterations in Zebrafish

et al. 2020

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“…The relationship between AD and APP and APOE has been well recognized. Other genes have also been reported in previous studies and these include CHRNB2, EGF, GLRB, HCN2, L1CAM, PDE2A, PIN1, SNAP25, and VEGFA (Chang et al, 2019;Cook et al, 2004;;Harris et al, 2017;Kraus et al, 2018;Miller et al, 2008;Thomas et al, 2016;Wang et al, 2017;Xu et al, 2017;Zhang et al, 2018).…”

Section: N-supporting

confidence: 72%

Targeted metabolomics study of early pathological features in hippocampus of triple transgenic Alzheimer’s disease male mice

Zhao

Chen

Iqbal

et al. 2020

J of Neuroscience Research

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Alzheimer's disease (AD) is a serious neurodegenerative disease in people of age 65 or above. The detailed etiology and pathogenesis of AD have not been elucidated yet. In this study, the hippocampi of 2‐ and 6‐month‐old triple transgenic Alzheimer's disease male mice and age–sex‐matched wild‐type (WT) mice were analyzed by using targeted metabolomics approach. Compared with WT mice, 24 and 60 metabolites were found with significant differences in 2‐ and 6‐month‐old AD mice. Among these, 14 metabolites were found common while 10 metabolites showed consistent variable trends in both groups. These differential metabolites are found associated with amino acid, lipid, vitamin, nucleotide‐related base, neurotransmitter and energy metabolisms, and oxidative stress. The results suggest that these differential metabolites might play a critical role in AD pathophysiology, and may serve as potential biomarkers for AD. Moreover, the results highlight the involvement of abnormal purine, pyrimidine, arginine, and proline metabolism, along with glycerophospholipid metabolism in early pathology of AD. For the first time, several differential metabolites are found to be associated with AD in this study. Targeted metabolomics can be used for rapid and accurate quantitative analysis of specific target metabolites associated with AD.

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“…In addition, interactions of L1CAM with growth factor receptors leading to receptor activation, is highly relevant for understanding cancer progression downstream of these receptors and has been studied in a much greater detail in non-cancerous cells [84,85,86,87] as compared to tumor cells [74]. Also, the roles of L1CAM interaction with ephrins [88], and potential downstream migration guidance regulation in tumors [89] and the occurrence and metabolic function of transmembrane-containing cleavage forms in mitochondria [90] in tumor cells await further investigation.…”

Section: Discussionmentioning

confidence: 99%

L1 Cell Adhesion Molecule in Cancer, a Systematic Review on Domain-Specific Functions

Maten

Reijnen

Pijnenborg

et al. 2019

IJMS

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L1 cell adhesion molecule (L1CAM) is a glycoprotein involved in cancer development and is associated with metastases and poor prognosis. Cellular processing of L1CAM results in expression of either full-length or cleaved forms of the protein. The different forms of L1CAM may localize at the plasma membrane as a transmembrane protein, or in the intra- or extracellular environment as cleaved or exosomal forms. Here, we systematically analyze available literature that directly relates to L1CAM domains and associated signaling pathways in cancer. Specifically, we chart its domain-specific functions in relation to cancer progression, and outline pre-clinical assays used to assess L1CAM. It is found that full-length L1CAM has both intracellular and extracellular targets, including interactions with integrins, and linkage with ezrin. Cellular processing leading to proteolytic cleavage and/or exosome formation results in extracellular soluble forms of L1CAM that may act through similar mechanisms as compared to full-length L1CAM, such as integrin-dependent signals, but also through distinct mechanisms. We provide an algorithm to guide a step-wise analysis on L1CAM in clinical samples, to promote interpretation of domain-specific expression. This systematic review infers that L1CAM has an important role in cancer progression that can be attributed to domain-specific forms. Most studies focus on the full-length plasma membrane L1CAM, yet knowledge on the domain-specific forms is a prerequisite for selective targeting treatment.

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A fragment of adhesion molecule L1 is imported into mitochondria, and regulates mitochondrial metabolism and trafficking

Cited by 19 publications

References 56 publications

Adhesion Molecule L1 Agonist Mimetics Protect Against the Pesticide Paraquat-Induced Locomotor Deficits and Biochemical Alterations in Zebrafish

Adhesion Molecule L1 Agonist Mimetics Protect Against the Pesticide Paraquat-Induced Locomotor Deficits and Biochemical Alterations in Zebrafish

Targeted metabolomics study of early pathological features in hippocampus of triple transgenic Alzheimer’s disease male mice

L1 Cell Adhesion Molecule in Cancer, a Systematic Review on Domain-Specific Functions

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