The Wiskott‐Aldrich syndrome: studies on a possible defect in mitochondrial ATP resynthesis in platelets

Akkerman, Jan Willem N.; Brederode, W van; Gorier, G.; Zegers, B. J. M.; Kuis, Wietse

doi:10.1111/j.1365-2141.1982.tb02819.x

Cited by 12 publications

(3 citation statements)

References 13 publications

(10 reference statements)

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“…The discovery of a metabolic defect in WAS MDMs is, to our knowledge, the first description of its kind. However, the idea of a metabolic defect in WAS platelets was inferred as early as 40–50 years ago, with several studies observing a paucity of mitochondria and impaired mitochondrial energy production ( Trung et al, 1975 ; Verhoeven et al, 1989 ; Akkerman et al, 1982 ; Obydennyi et al, 2020 ). Although as yet unstudied, extending these metabolic defects to other immune cell lineages may go some way to explaining other immunophenotypic features of WAS including T cell anergy, progressive reduction in B and T lymphocytes with age and increasing development of autoinflammatory symptoms.…”

Section: Discussionmentioning

confidence: 99%

Wiskott Aldrich syndrome protein regulates non-selective autophagy and mitochondrial homeostasis in human myeloid cells

Rivers

Rai

Lötscher

et al. 2020

eLife

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The actin cytoskeletal regulator Wiskott Aldrich syndrome protein (WASp) has been implicated in maintenance of the autophagy-inflammasome axis in innate murine immune cells. Here, we show that WASp deficiency is associated with impaired rapamycin-induced autophagosome formation and trafficking to lysosomes in primary human monocyte-derived macrophages (MDMs). WASp reconstitution in vitro and in WAS patients following clinical gene therapy restores autophagic flux and is dependent on the actin-related protein complex ARP2/3. Induction of mitochondrial damage with CCCP, as a model of selective autophagy, also reveals a novel ARP2/3-dependent role for WASp in formation of sequestrating actin cages and maintenance of mitochondrial network integrity. Furthermore, mitochondrial respiration is suppressed in WAS patient MDMs and unable to achieve normal maximal activity when stressed, indicating profound intrinsic metabolic dysfunction. Taken together, we provide evidence of new and important roles of human WASp in autophagic processes and immunometabolic regulation, which may mechanistically contribute to the complex WAS immunophenotype.

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Section: Discussionmentioning

confidence: 99%

Wiskott Aldrich syndrome protein regulates non-selective autophagy and mitochondrial homeostasis in human myeloid cells

Rivers

Rai

Lötscher

et al. 2020

eLife

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“…Stroke and stroke-like episodes are frequent complications in mitochondriopathy which is a rare disorder of the mitochondrial oxidative metabolism in diverse cell types (23). Human platelets contain mitochondria which play an important role for energy metabolism by the synthesis of ATP which is necessary for normal platelet responsiveness (24,25). To the best of our knowledge we conclude from the present investigation for the first time that exercise induces a decrease of intraplatelet ATP concentration in patients with mitochondriopathy and stroke.…”

Section: Discussionmentioning

confidence: 99%

Platelet function in mitochondriopathy with stroke and stroke-like episodes

Kotzailias¹,

Finsterer²,

Zellner³

et al. 2004

Thromb Haemost

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Stroke and stroke-like episodes are frequent complications in mitochondriopathy, particularly in MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke like episodes) which is a disorder of the mitochondrial oxidative metabolism in diverse cell types. To clarify a possible pathological aspect of stroke in these patients, we investigated platelet function before and after physical exercise. Ten patients with mitochondriopathy and stroke and ten healthy sex and age matched controls were investigated in an analyst blinded, prospective cross-sectional trial. Exercise decreased intraplatelet adenosine triphosphate (ATP) concentrations by -22% from baseline in patients with mitochondriopathy (p<0.01 between groups) while exercise increased ATP-levels by 28% healthy controls (p=0.01 vs baseline). Thrombin receptor activating peptide (TRAP) stimulated P-selectin expression increased up to 50% (p<0.05) in healthy subjects following exercise compared to 39% (p>0.05) in patients with mitochondriopathy. Exercise trendwise decreased platelet plug formation under shear stress by 24% in patients as measured by the platelet function analyzer PFA-100(R). Tromboelastography showed firm thrombus formation and delayed lysis in patients following exercise. In conclusion, this trial has shown that ATP depletion during and after exercise probably accounts for a defective oxidative metabolism in platelets of patients with mitochondriopathy and stroke. This might induce decreased platelet function in these patients but fails to explain the increased stroke rate. Therefore other mechanisms seem to be etiologically involved in the pathogenesis of stroke in patients with mitochondriopathy.

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“…The subjects studied were two patients with WAS, referred to as patients 1 and 2; 14 and 6 years old, respectively, who have been presented previously (patients Ill-a and Il-a, respectively* in ref. 7). Other subjects were the mothers of patients 1 and 2 (obligate carriers), a sister of patient 2 (possible carrier) and a patient with an isolated hexokinase type 1 deficiency, who has been described elsewhere (8,9).…”

Section: Patientsmentioning

confidence: 99%

Impaired Energy Metabolism in Platelets from Patients with Wiskott-Aldrich Syndrome

Aj¹,

Ie²,

H³

et al. 1989

Thromb Haemost

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SummaryThe platelet function defect seen in patients with Wiskott- Aldrich syndrome (WAS) has been ascribed to abnormal mitochondrial energy generation. The present study reveals a reduced energy content and low adenylate energy charge in platelets from two WAS-patients. Energy consumption in the resting platelets is slightly beyond the normal range, especially when ATP-resynthesis is primarily glycolytic. When platelets are stimulated with thrombin, the increase in energy consumption is 40-60% lower than in controls, both when energy is produced in glycolysis as when the mitochondria supply most of the energy. Analysis of the electron transport chain reveals no abnormalities. In contrast, the balance between glycolytic and mitochondrial ATP resynthesis is disturbed with a lowered contribution of oxidative ATP production. No such abnormalities are found in two WAS-carriers with the exception of a slight impairment in energy consumption during stimulation with thrombin. Thus, the platelet malfunction in WAS may be caused by a defect in the regulation of energy generation.

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The Wiskott‐Aldrich syndrome: studies on a possible defect in mitochondrial ATP resynthesis in platelets

Cited by 12 publications

References 13 publications

Wiskott Aldrich syndrome protein regulates non-selective autophagy and mitochondrial homeostasis in human myeloid cells

Wiskott Aldrich syndrome protein regulates non-selective autophagy and mitochondrial homeostasis in human myeloid cells

Platelet function in mitochondriopathy with stroke and stroke-like episodes

Impaired Energy Metabolism in Platelets from Patients with Wiskott-Aldrich Syndrome

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