Mitochondrial respiratory chain deficiency inhibits lysosomal hydrolysis

Fernández-Mosquera, Lorena; Yambire, King Faisal; Couto, Renata; Pereyra, Leonardo Gabriel; Pabis, Kamil; Ponsford, Amy H.; Diogo, Cátia V.; Stagi, Massimiliano; Milošević, Ira; Raimundo, Nuno

doi:10.1080/15548627.2019.1586256

Cited by 95 publications

(93 citation statements)

References 80 publications

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“…In addition to the mitochondrial alterations, TEM also detected a gradual thickening of the nuclear membrane, the integrity of which was altered in the drug-treated parasites compared to the untreated specimens as it appeared partially separated, creating a wider distance between nucleus and surrounding cytoplasm. Such a compartmentalization of the cytoplasm could possibly be an effect of autophagy upon chronic mitochondrial respiratory chain impairment (32). However, this needs to be further investigated.…”

Section: Discussionmentioning

confidence: 97%

Activities of Endochin-Like Quinolones Against in vitro Cultured Besnoitia besnoiti Tachyzoites

et al. 2020

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Endochin-like quinolones (ELQs) potently inhibit the proliferation of Plasmodium, Toxoplasma, Neospora, and Babesia by targeting the cytochrome b Qo and Qi sites and interfering with oxidative phosphorylation and pyrimidine biosynthesis. The activities of 14 different ELQs were assessed against B. besnoiti tachyzoites grown in human foreskin fibroblasts (HFF) by quantitative real time PCR. The values for 50% proliferation inhibition (IC50) of five ELQs were determined in a 3-days growth assay after an initial screen of 12 ELQs at 0.01, 0.1, and 1 µM. The IC50s of ELQ-121,-136, and-316 were 0.49, 2.36, and 7.97 nM, respectively. The IC50s of ELQs tested against B. besnoiti were higher than IC50s previously observed for P. falciparum and T. gondii. However, the B. besnoiti cytochrome b sequence and the predicted Qo and Qi ELQ binding sites in the Toxoplasma, Neospora, and Besnoitia cytochrome b are virtually identical, suggesting that the differences in ELQ susceptibility are not due to variations in the substrate binding sites. TEM of ELQ-treated parasites primarily demonstrated alterations within the parasite mitochondrion, profound thickening of the nuclear membrane, as well as increased vacuolization within the tachyzoite cytoplasm. Long-term treatment assays of intracellular B. besnoiti with ELQs for up to 20 days followed by the release of drug pressure caused a substantial delay in parasite growth and proliferation while ELQs were present, but parasite proliferation resumed days after ELQs were removed. Interestingly, structural alterations persisted after ELQ removal and parasite proliferation was slowed. These findings provide a basis for further in vivo studies of ELQs as therapeutic options against B. besnoiti infection.

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Section: Discussionmentioning

confidence: 97%

Activities of Endochin-Like Quinolones Against in vitro Cultured Besnoitia besnoiti Tachyzoites

et al. 2020

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“…Therefore, we consider that mitochondrial fragmentation keeps low metabolism levels to reduce cytotoxicity in MD fibroblasts. Mitochondrial fission promotes clearance of damaged mitochondria through a form of autophagy known as mitophagy [42], whereas perturbation of mitochondrial dynamics has been shown to cause lysosomal dysfunction and autophagy impairment [43], and chronic mitochondrial defects trigger general impairment of autophagy and lysosomes to avoid complete degradation of the mitochondrial network [44,45]. Drp1 knockdown or treatment with bafilomycin A1, an autophagic flux inhibitor, significantly increased the amount of mitochondria in MD fibroblasts (Supplementary Figure S2A-C).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Dynamics Regulation in Skin Fibroblasts from Mitochondrial Disease Patients

et al. 2020

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Mitochondria are highly dynamic organelles that constantly fuse, divide, and move, and their function is regulated and maintained by their morphologic changes. Mitochondrial disease (MD) comprises a group of disorders involving mitochondrial dysfunction. However, it is not clear whether changes in mitochondrial morphology are related to MD. In this study, we examined mitochondrial morphology in fibroblasts from patients with MD (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and Leigh syndrome). We observed that MD fibroblasts exhibited significant mitochondrial fragmentation by upregulation of Drp1, which is responsible for mitochondrial fission. Interestingly, the inhibition of mitochondrial fragmentation by Drp1 knockdown enhanced cellular toxicity and led to cell death in MD fibroblasts. These results suggest that mitochondrial fission plays a critical role in the attenuation of mitochondrial damage in MD fibroblasts.Biomolecules 2020, 10, 450 2 of 13 respiratory chain complexes [7]. However, in multiple cases, the exact genetic cause of Leigh syndrome remains unknown [8]. Currently, there is no cure or effective treatment for MD, but recent research has shown the potential benefits of some approaches, at least in preclinical in vivo models [9][10][11]. Many researchers assume that both bulk and mitochondrial autophagy play protective roles in MD because the accumulation of damaged mitochondria and other toxic aggregates causes deterioration of the pathophysiology of the cell [12]. Preclinical studies suggest that a potential therapeutic target of disease progression is the mammalian target of rapamycin (mTOR) pathway, a biological route fundamental for regulating cell metabolism and physiology [13]. In mice models of Leigh syndrome, treatment with rapamycin, an mTOR inhibitor, extended lifespan and reduced disease progression and severity [14]. Civiletto et al. provided evidence that rapamycin induces improvements in mitochondrial function and ultrastructure, indicating powerful clearance of dysfunctional organelles via activation of autophagic flux in skeletal muscle.Mitochondria are highly dynamic organelles that continuously fuse, divide, and move, and mitochondrial function is controlled and maintained by these morphologic changes. Mitochondrial fission is specifically mediated by dynamin-related guanosine triphosphatase (GTPase) protein 1 (Drp1); in addition, dynamin-related GTPases mitofusin (Mfn) and optic atrophy 1 (OPA1) are associated with the outer and inner mitochondrial membranes, respectively, and mediate fusion of these membranes [15][16][17][18][19]. The most direct consequence of mitochondrial division and fusion is the change in size of the mitochondria [20][21][22]. Mitochondrial fission via Drp1 has been thought to regulate mitophagy by dividing mitochondria into fragments suitable for autophagosome engulfment [23][24][25] and/or separating damaged subdomains of mitochondria for elimination [26]. Mitochondrial fusion enables efficient mixing of m...

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“…DQ-BSA Assay. DQ Green BSA (Life Technologies) was used to measure lysosomal protease activity in cells as described previously (67), with slight modifications described in SI Appendix, Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

Lysosomal degradation products induce Coxiella burnetii virulence

Newton

Thomas

Reed

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Coxiella burnetiiis an intracellular pathogen that replicates in a lysosome-like vacuole through activation of a Dot/Icm-type IVB secretion system and subsequent translocation of effectors that remodel the host cell. Here a genome-wide small interfering RNA screen and reporter assay were used to identify host proteins required for Dot/Icm effector translocation. Significant, and independently validated, hits demonstrated the importance of multiple protein families required for endocytic trafficking of theC. burnetii-containing vacuole to the lysosome. Further analysis demonstrated that the degradative activity of the lysosome created by proteases, such as TPP1, which are transported to the lysosome by receptors, such as M6PR and LRP1, are critical forC. burnetiivirulence. Indeed, theC. burnetiiPmrA/B regulon, responsible for transcriptional up-regulation of genes encoding the Dot/Icm apparatus and a subset of effectors, induced expression of a virulence-associated transcriptome in response to degradative products of the lysosome. Luciferase reporter strains, and subsequent RNA-sequencing analysis, demonstrated that particular amino acids activate theC. burnetiiPmrA/B two-component system. This study has further enhanced our understanding ofC. burnetiipathogenesis, the host–pathogen interactions that contribute to bacterial virulence, and the different environmental triggers pathogens can sense to facilitate virulence.

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Mitochondrial respiratory chain deficiency inhibits lysosomal hydrolysis

Cited by 95 publications

References 80 publications

Activities of Endochin-Like Quinolones Against in vitro Cultured Besnoitia besnoiti Tachyzoites

Activities of Endochin-Like Quinolones Against in vitro Cultured Besnoitia besnoiti Tachyzoites

Mitochondrial Dynamics Regulation in Skin Fibroblasts from Mitochondrial Disease Patients

Lysosomal degradation products induce Coxiella burnetii virulence

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