Aging Immunity to Extracellular Mitochondria Exacerbates Vascular Cognitive Impairment After Stroke

Massachusetts General Hospital, Boston MA

Investigators

Abstract

Aging immunity to extracellular mitochondria exacerbates vascular cognitive impairment after stroke The pathogenic mechanisms of vascular contributions to cognitive impairment and dementia (VCID) are poorly understood. Neurovascular inflammation is a key driver of VCID. There is also a large literature implicating mitochondrial dysfunction in VCID. Is it possible that these two phenomena are linked? Over the past 5 years, our lab has described unexpected pathways of extracellular mitochondria in stroke. Here, we build on our accumulating data to propose a new idea. In the young brain, healthy extracellular mitochondria are recycled by microglia/macrophages as part of neurovascular protective response after stroke. But in the aged brain, age-related changes in immune function alters this recycling process and results in dysfunctional mitochondria secretion that can no longer protect neurons and endothelial cells after stroke. Our pilot data suggest that (i) engulfed healthy mitochondria produce recycling cargo, consisting of SQSTM1- LC3-Rab27 in young macrophage/microglia, (ii) blocking the system inversely promotes lysosomal degradation of engulfed mitochondria, antigen presentation and opsonin-tagged mitochondria secretion, (iii) the protein complex also regulates neuroprotective mitochondria transfer, whereas inhibiting Rab27a diminished the effect, (iv) aging downregulates SQSTM1 in the spleen and increases complement C4+ mitochondria in plasma, (v) the opsonized mitochondria may be abundant in human thrombus and exacerbate vascular inflammation and neuronal death after transient focal cerebral ischemia, but (vi) supplementing SQSTM1 protein and healthy mitochondria reverses the productions of complement C4+ mitochondria, anticardiolipin antibody (ACA) IgG and decrease vascular inflammation and neuronal death signals post-stroke, (vii) all methods to dissect these mechanisms (molecular and genetic tools, in vivo model, RNA-seq, etc) are feasible in our collaborating labs. Building on these pilot data, we propose the specific hypothesis that SQSTM1-LC3-Rab27 complex regulates mitochondrial lysosomal escape and recycling in young macrophage/microglia. Age-associated decline of SQSTM1 increases opsonized “pathogenic” extracellular mitochondria that accelerate vascular inflammation and VCID after focal cerebral ischemia. Thus, rejuvenating aging macrophage/microglia by boosting SQSTM1- mediated mechanism should recover “healthy” extracellular mitochondria post-stroke and ameliorate VCID. We have 3 specific aims. In Aim 1, we will investigate the mechanisms of engulfed mitochondrial recycling in vitro. In Aim 2, we will assess post-stroke neurovascular inflammation driven by extracellular mitochondria in aging. In Aim 3, we will perform gain- and loss-of-function modification of mitochondria recycling to investigate the relevance for vascular cognitive impairment in young and older male or female mice after focal cerebral ischemia. This project should define a novel mechanism of extracellular mitochondria immune recycling that should open up entirely different therapeutic avenues for post-stroke motor and cognitive impairments driven by aging.