ECSIT prevents Alzheimer’s disease pathology by regulating neuronal mitochondrial ROS and mitophagy

Abstract

Altered mitochondrial fitness is a potential triggering factor in Alzheimer’s disease (AD). Mitochondrial quality control pathways are dysfunctional and mitochondrially-derived reactive oxygen species (mROS) levels are increased in AD patient brains. However, the pathways responsible for dysregulated mROS accumulation have remained relatively unclear. In this study, we demonstrate that levels of ECSIT, a mitochondrial oxidative phosphorylation (OxPhos) complex I (CI)-associated protein, are reduced in AD-affected brains. Neuronal ECSIT downregulation increased mROS generation and impaired mitophagy of defective mitochondria. Consequently, decreasing neuronal ECSIT caused AD-like changes, including memory loss and neuropathology. In contrast, augmented neuronal expression of ECSIT protected against the development of an AD-like phenotype. Decreased levels of ECSIT in AD patient brains therefore likely contribute to oxidative stress, neuroinflammation and AD pathogenesis.

GSTT1 as a Predictive Marker and Enhancer for Osteogenic Potential of Human Adipose-Derived Stromal/Stem Cells

“…4D, E), mitochondria-related ECSIT gene and metabolism-related ST3GAL5 and ErbB2 genes are known to influence osteogenic differentiation. (57)(58)(59)(60)(61)(62) ECSIT is a mitochondrial complex I (CI)-related protein that regulates the production of mitochondrial mROS after binding to Toll-like receptors. (57)(58)(59) ECSIT also constitutively associates with Smad4 and Smad1.…”

“…(57)(58)(59)(60)(61)(62) ECSIT is a mitochondrial complex I (CI)-related protein that regulates the production of mitochondrial mROS after binding to Toll-like receptors. (57)(58)(59) ECSIT also constitutively associates with Smad4 and Smad1. Therefore, ECSIT can affect osteogenic differentiation via two pathways.…”

“…Therefore, ECSIT can affect osteogenic differentiation via two pathways. (57)(58)(59) ST3GAL5 is a key enzyme and direct target of Runx transcriptional regulation (Runx1, 2, 3) consistent with survival and apoptosis resistance as well as osteogenic differentiation. (60) ErbB2 is a member of the human epidermal growth factor receptor and one of the target genes of YAP protein regulating cell proliferation.…”