Loss of the mitochondrial kinase PINK1 does not alter platelet function.

PTEN-induced putative kinase (PINK) 1 is regarded as a master regulator of cellular mitophagy such that loss of function mutations contribute to early onset Parkinson's disease, through aberrant mitochondrial control and function. Mitochondrial function is key to platelet procoagulant activity, controlling the haemostatic response to vessel injury, but can also predispose blood vessels to thrombotic complications. Here, we sought to determine the role of PINK1 in platelet mitochondrial health and function using PINK1 knockout (KO) mice. The data largely show an absence of such a role. Haematological analysis of blood counts from KO mice was comparable to wild type. Quantification of mitochondrial mass by citrate synthase activity assay or expression of mitochondrial markers were comparable, suggesting normal mitophagy in KO platelets. Analysis of mitochondrial permeability transition pore opening, changes in mitochondrial membrane potential and calcium signalling to platelet activation were unaffected by loss of PINK1, whereas subtle enhancements of activation-induced reactive oxygen species were detected. Platelet aggregation, integrin activation, α- and dense granule secretion and phosphatidylserine exposure were unaltered in KO platelets while mouse tail bleeding responses were similar to wild type. Together these results demonstrate that PINK1 does not regulate basal platelet mitophagy and is dispensable for platelet function.

Skeletal Site-specific Changes in Bone Mass in a Genetic Mouse Model for Human 15q11-13 Duplication Seen in Autism.

Children suffering from autism have been reported to have low bone mineral density and increased risk for fracture, yet the cellular origin of the bone phenotype remains unknown. Here we have utilized a mouse model of autism that duplicates 6.3 Mb region of chromosome 7 (Dp/+) corresponding to a region of chromosome 15q11-13, duplication of which is recurrent in humans to characterize the bone phenotype. Paternally inherited Dp/+ (patDp/+) mice showed expected increases in the gene expression in bone, normal postnatal growth and body weight acquisition compared to the littermate controls. Four weeks-old patDp/+ mice develop a low bone mass phenotype in the appendicular but not the axial skeleton compared to the littermate controls. This low bone mass in the mutant mice was secondary to a decrease in the number of osteoblasts and bone formation rate while the osteoclasts remained relatively unaffected. Further in vitro cell culture experiments and gene expression analysis revealed a major defect in the proliferation, differentiation and mineralization abilities of patDp/+ osteoblasts while osteoclast differentiation remained unchanged compared to controls. This study therefore characterizes the structural and cellular bone phenotype in a mouse model of autism that can be further utilized to investigate therapeutic avenues to treat bone fractures in children with autism.

Hypertension: a problem of organ blood flow supply-demand mismatch.

This review introduces a new hypothesis that sympathetically mediated hypertensive diseases are caused, in the most part, by the activation of visceral afferent systems that are connected to neural circuits generating sympathetic activity. We consider how organ hypoperfusion and blood flow supply-demand mismatch might lead to both sensory hyper-reflexia and aberrant afferent tonicity. We discuss how this may drive sympatho-excitatory-positive feedback and extend across multiple organs initiating, or at least amplifying, sympathetic hyperactivity. The latter, in turn, compounds the challenge to sufficient organ blood flow through heightened vasoconstriction that both maintains and exacerbates hypertension.