Coenzyme A precursors flow from mother to zygote and from microbiome to host

Yu, Yi; Zwaag, Marianne van der; Wedman, Jouke Jan; Permentier, Hjalmar P.; Plomp, Niels; Jia, Xiu; Kanon, Bart; Eggens-Meijer, Ellie; Buist, Girbe; Harmsen, Hermie J. M.; Salles, Joana Falcão; Wertheim, Bregje; Hayflick, Susan J.; Strauss, Erick; Grzeschik, Nicola A.; Schepers, Hein; Sibon, Ody C. M.

doi:10.1016/j.molcel.2022.05.006

Cited by 7 publications

(5 citation statements)

References 72 publications

(84 reference statements)

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“…Furthermore, a process of transcriptional adaptation elicited by the degradation of the mutant transcripts via the mRNA surveillance pathway could modify the expression of genes not directly involved in the phosphorylation of vitamin B5 but contributing to a compensatory biochemical adjustment [ 49 ]. Interestingly, also the microbiome could concur to the maintenance of adequate levels of CoA both in tissues of adult mutant fish and in the yolk of embryos, providing intermediates downstream the first phosphorylation step catalyzed by Pank2 [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Bi-Allelic Mutations in Zebrafish pank2 Gene Lead to Testicular Atrophy and Perturbed Behavior without Signs of Neurodegeneration

Mignani

Zizioli

Khatri

et al. 2022

IJMS

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Coenzyme A (CoA) is an essential cofactor in all living organisms, being involved in a large number of chemical reactions. Sequence variations in pantothenate kinase 2 (PANK2), the first enzyme of CoA biosynthesis, are found in patients affected by Pantothenate Kinase Associated Neurodegeneration (PKAN), one of the most common forms of neurodegeneration, with brain iron accumulation. Knowledge about the biochemical and molecular features of this disorder has increased a lot in recent years. Nonetheless, the main culprit of the pathology is not well defined, and no treatment option is available yet. In order to contribute to the understanding of this disease and facilitate the search for therapies, we explored the potential of the zebrafish animal model and generated lines carrying biallelic mutations in the pank2 gene. The phenotypic characterization of pank2-mutant embryos revealed anomalies in the development of venous vascular structures and germ cells. Adult fish showed testicular atrophy and altered behavioral response in an anxiety test but no evident signs of neurodegeneration. The study suggests that selected cell and tissue types show a higher vulnerability to pank2 deficiency in zebrafish. Deciphering the biological basis of this phenomenon could provide relevant clues for better understanding and treating PKAN.

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Section: Discussionmentioning

confidence: 99%

Bi-Allelic Mutations in Zebrafish pank2 Gene Lead to Testicular Atrophy and Perturbed Behavior without Signs of Neurodegeneration

Mignani

Zizioli

Khatri

et al. 2022

IJMS

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“…Alternatively, it is conceivable that C. neoformans utilizes a derivative of PA within the host phagolysosome. The established alternatives to PA in CoA biosynthesis involve the utilization of 4'-phosphopantetheine as a nexus metabolite [119,120]. Notably, this specific PA derivative is both membrane-permeable and stable in serum.…”

Section: Plos Pathogensmentioning

confidence: 99%

Kicking sleepers out of bed: Macrophages promote reactivation of dormant Cryptococcus neoformans by extracellular vesicle release and non-lytic exocytosis

de Castro,

Marina,

Sturny-Leclère

et al. 2023

PLoS Pathog

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Macrophages play a key role in disseminated cryptococcosis, a deadly fungal disease caused by Cryptococcus neoformans. This opportunistic infection can arise following the reactivation of a poorly characterized latent infection attributed to dormant C. neoformans. Here, we investigated the mechanisms underlying reactivation of dormant C. neoformans using an in vitro co-culture model of viable but non-culturable (VBNC; equivalent of dormant) yeast cells with bone marrow-derived murine macrophages (BMDMs). Comparative transcriptome analysis of BMDMs incubated with log, stationary phase or VBNC cells of C. neoformans showed that VBNC cells elicited a reduced transcriptional modification of the macrophage but retaining the ability to regulate genes important for immune response, such as NLRP3 inflammasome-related genes. We further confirmed the maintenance of the low immunostimulatory capacity of VBNC cells using multiplex cytokine profiling, and analysis of cell wall composition and dectin-1 ligands exposure. In addition, we evaluated the effects of classic (M1) or alternative (M2) macrophage polarization on VBNC cells. We observed that intracellular residence sustained dormancy, regardless of the polarization state of macrophages and despite indirect detection of pantothenic acid (or its derivatives), a known reactivator for VBNC cells, in the C. neoformans-containing phagolysosome. Notably, M0 and M2, but not M1 macrophages, induced extracellular reactivation of VBNC cells by the secretion of extracellular vesicles and non-lytic exocytosis. Our results indicate that VBNC cells retain the low immunostimulatory profile required for persistence of C. neoformans in the host. We also describe a pro-pathogen role of macrophage-derived extracellular vesicles in C. neoformans infection and reinforce the impact of non-lytic exocytosis and the macrophage profile on the pathophysiology of cryptococcosis.

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“…Moreover, endogenous 4′-phosphopantetheine is present in mammalian serum, which suggests that it can be transferred between cells and tissues and presumably serve as an alternate source for CoA synthesis [27]. Newly published data show that CoA intermediates, including 4′phosphopantetheine, are transferred from mother to progeny and from gut microbiome to the host [74], further bolstering the importance of this intermediate in supporting a widening range of functions.…”

Section: Where Is Coa Synthesized?mentioning

confidence: 99%