Deficient mitophagy pathways in sickle cell disease

Martino, Suella; Arlet, Jean‐Benoît; Odièvre, Marie‐Hélène; Jullien, Vincent; Moras, Martina; Hattab, Claude; Lefèbvre, Thibaud; Gouya, Laurent; Ostuni, Mariano A.; Lefevre, Sophie D.; Kim, Caroline Le Van

doi:10.1111/bjh.17416

Cited by 18 publications

(27 citation statements)

References 13 publications

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“…Supporting these reports, we observed here an increase in autophagosome abundance and size in OrthoE (Figure 5) that might reflect an increase in autophagic activity within the cell. Defect in proper mitochondria degradation leads to the maintenance of mitochondria in mature circulating red blood cells, as recently described for SCD or for SLE (Jagadeeswaran et al, 2017;Caielli et al, 2021;Martino et al, 2021). While not completely elucidated, this defective mitochondrial clearance might participate in the pathophysiology of the diseases.…”

Section: Discussionmentioning

confidence: 79%

“…Mitochondrial retention was previously associated with deficient mitophagy following mitophagy receptors knockdown in mice ( Sandoval et al, 2008 ) and humans ( Moras et al, 2022 ). During the last 5 years, growing evidences were reported correlating autophagy deficiencies and particularly mitophagy defaults with different pathologies as sickle cell disease (SCD) or systemic lupus erythematosus (SLE; Jagadeeswaran et al, 2017 ; Caielli et al, 2021 ; Martino et al, 2021 ). Moreover, a novel atypical anemia was associated with the presence of miscellaneous membranous structure on patients’ reticulocytes and mature red blood ( Ru et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

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Transmission Electron Microscopy to Follow Ultrastructural Modifications of Erythroblasts Upon ex vivo Human Erythropoiesis

et al. 2022

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Throughout mammal erythroid differentiation, erythroblasts undergo enucleation and organelle clearance becoming mature red blood cell. Organelles are cleared by autophagic pathways non-specifically targeting organelles and cytosolic content or by specific mitophagy targeting mitochondria. Mitochondrial functions are essential to coordinate metabolism reprogramming, cell death, and differentiation balance, and also synthesis of heme, the prosthetic group needed in hemoglobin assembly. In mammals, mitochondria subcellular localization and mitochondria interaction with other structures as endoplasmic reticulum and nucleus might be of importance for the removal of the nucleus, that is, the enucleation. Here, we aim to characterize by electron microscopy the changes in ultrastructure of cells over successive stages of human erythroblast differentiation. We focus on mitochondria to gain insights into intracellular localization, ultrastructure, and contact with other organelles. We found that mitochondria are progressively cleared with a significant switch between PolyE and OrthoE stages, acquiring a rounded shape and losing contact sites with both ER (MAM) and nucleus (NAM). We studied intracellular vesicle trafficking and found that endosomes and MVBs, known to be involved in iron traffic and heme synthesis, are increased during BasoE to PolyE transition; autophagic structures such as autophagosomes increase from ProE to OrthoE stages. Finally, consistent with metabolic switch, glycogen accumulation was observed in OrthoE stage.

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Section: Discussionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Transmission Electron Microscopy to Follow Ultrastructural Modifications of Erythroblasts Upon ex vivo Human Erythropoiesis

et al. 2022

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“…reports suggesting that incomplete removal of mitochondria is associated with defects in mitophagy-related gene function during erythropoiesis. 16,47 As sickled RBCs readily haemolyze, both reticulocytes and mature RBCs could be a source of the cell-free mitochondria observed in the plasma of patients with SCD. 17 Of note, individuals with sickle trait have similar frequencies of reticulocytes and mitochondrialpositive mature RBCs as compared with healthy blood donors, suggesting that two copies of the mutated beta globin gene are required to affect mitochondrial retention or, perhaps, an inherited gene in linkage disequilibrium is involved.…”

Section: (B) ( C) (D)mentioning

confidence: 99%

Retention of functional mitochondria in mature red blood cells from patients with sickle cell disease

et al. 2022

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Sickle cell disease (SCD) is an inherited blood disorder characterized by sickled red blood cells (RBCs), which are more sensitive to haemolysis and can contribute to disease pathophysiology. Although treatment of SCD can include RBC transfusion, patients with SCD have high rates of alloimmunization. We hypothesized that RBCs from patients with SCD have functionally active mitochondria and can elicit a type 1 interferon response. We evaluated blood samples from more than 100 patients with SCD and found elevated frequencies of mitochondria in reticulocytes and mature RBCs, as compared to healthy blood donors. The presence of mitochondria in mature RBCs was confirmed by flow cytometry, electron microscopy, and proteomic analysis. The mitochondria in mature RBCs were metabolically competent, as determined by enzymatic activities and elevated levels of mitochondria-derived metabolites.Metabolically-active mitochondria in RBCs may increase oxidative stress, which could facilitate and/or exacerbate SCD complications. Coculture of mitochondriapositive RBCs with neutrophils induced production of type 1 interferons, which are known to increase RBC alloimmunization rates. These data demonstrate that mitochondria retained in mature RBCs are functional and can elicit immune responses, suggesting that inappropriate retention of mitochondria in RBCs may play an underappreciated role in SCD complications and be an RBC alloimmunization risk factor.

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“…However, further studies are required to understand the spatiotemporal activation of these two pathways in physiological conditions. Mitochondrial elimination by mitophagy during the maturation of red blood cells is an important process, and its deficiency is associated with many diseases such as myelodysplastic syndromes anemia and sickle cell disease (118,119). This is why investigating the mechanisms and actors implicated in the clearance of mitochondria from red blood cells is necessary to unravel how this process is compromised in patients, and may help developing new therapeutic strategies.…”

Section: Mechanisms Of Mitophagy In Red Blood Cellsmentioning

confidence: 99%

Mitochondrial transport, partitioning, and quality control at the heart of cell proliferation and fate acquisition

Sharma

Chafik

Bertolin

2022

American Journal of Physiology-Cell Physiology

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Mitochondria are essential to cell homeostasis, and alterations in mitochondrial distribution, segregation or turnover have been linked to complex pathologies such as neurodegenerative diseases or cancer. Understanding how these functions are coordinated in specific cell types is a major challenge to discover how mitochondria globally shape cell functionality. In this review, we will first describe how mitochondrial transport and dynamics are regulated throughout the cell cycle in yeast and in mammals. Second, we will explore the functional consequences of mitochondrial transport and partitioning on cell proliferation, fate acquisition, stemness, and on the way cells adapt their metabolism. Last, we will focus on how mitochondrial clearance programs represent a further layer of complexity for cell differentiation, or in the maintenance of stemness. Defining how mitochondrial transport, dynamics and clearance are mutually orchestrated in specific cell types may help our understanding of how cells can transition from a physiological to a pathological state.

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Deficient mitophagy pathways in sickle cell disease

Abstract: emie et autres maladies rares du Globule Rouge et de l' erythropo€ ı ese, AP-HP, Hôpital Europ een Georges-Pompidou,

Cited by 18 publications

References 13 publications

Transmission Electron Microscopy to Follow Ultrastructural Modifications of Erythroblasts Upon ex vivo Human Erythropoiesis

Transmission Electron Microscopy to Follow Ultrastructural Modifications of Erythroblasts Upon ex vivo Human Erythropoiesis

Retention of functional mitochondria in mature red blood cells from patients with sickle cell disease

Mitochondrial transport, partitioning, and quality control at the heart of cell proliferation and fate acquisition

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