Compartment-specific mitochondrial unfolded protein response in Alzheimer’s disease
Description: Mitochondria, the energy-producing centers of cells, are essential for brain health but are often damaged in Alzheimer’s disease (AD), driving memory loss and neuronal death. To counter stress, mitochondria activate a repair mechanism called the mitochondrial unfolded protein response (UPRmt) to maintain their health. However, the mitochondrial matrix (UPRmt-MM) and intermembrane space (UPRmt-IMS) have distinct stress response mechanisms, and their roles in AD remain unclear. This study takes a novel compartment-specific approach to investigate how UPRmt-MM and UPRmt-IMS activation influence mitochondrial function, neurodegeneration, and disease progression in AD. Using cutting-edge in vivo AD models, we will induce proteotoxic stress in MM (mutant ornithine transcarbamylase) and IMS (mutant EndoG) to evaluate transcriptional and protein-level changes, age dependent cognitive decline, amyloid-ß/tau pathologies and neuronal loss (Aim 1) as well as mitochondrial bioenergetics, oxidative stress, and cell death pathways (Aim 2). This study will determine whether compartment-specific UPRmt activation is an early protective response or a maladaptive driver of AD pathology. If UPRmt exacerbates AD progression, it suggests a maladaptive role; if protective, it presents a novel therapeutic target. This innovative focus on compartmentalized UPRmt signaling fills a critical gap in understanding mitochondrial dysfunction in AD and will guide precision-targeted therapies to restore mitochondrial homeostasis. Beyond AD, these findings have transformative potential to inform treatments for other diseases linked to mitochondrial dysfunction, including cardiovascular disorders, cancer, and infections, amplifying the study’s broad impact across medical disciplines
Funder: American Heart Association
Amount: $200,000
Funding type: research
Funder scheme: Innovative Project Award
Start date: 2025-07-01
End date: 2027-06-30
Investigators: Pooja Jadiya, Pooja Jadiya
Institution: Wake Forest University Health Sciences
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Funded outputs count: 2
Funder award ID: 25IPA1453119
OpenAlex ID: G1121154335