Deregulation of Mitochondrial Calcium Handling Due to Presenilin Loss Disrupts Redox Homeostasis and Promotes Neuronal Dysfunction

Abstract

Mitochondrial dysfunction and oxidative stress are major contributors to the pathophysiology of neurodegenerative diseases, including Alzheimer’s disease (AD). However, the mechanisms driving mitochondrial dysfunction and oxidative stress are unclear. Familial AD (fAD) is an early onset form of AD caused primarily by mutations in the presenilin-encoding genes. Previously, using Caenorhabditis elegans as a model system to study presenilin function, we found that loss of C. elegans presenilin orthologue SEL-12 results in elevated mitochondrial and cytosolic calcium levels. Here, we provide evidence that elevated neuronal mitochondrial generated reactive oxygen species (ROS) and subsequent neurodegeneration in sel-12 mutants are a consequence of the increase of mitochondrial calcium levels and not cytosolic calcium levels. We also identify mTORC1 signaling as a critical factor in sustaining high ROS in sel-12 mutants in part through its repression of the ROS scavenging system SKN-1/Nrf. Our study reveals that SEL-12/presenilin loss disrupts neuronal ROS homeostasis by increasing mitochondrial ROS generation and elevating mTORC1 signaling, which exacerbates this imbalance by suppressing SKN-1/Nrf antioxidant activity.

C. elegans Presenilin Mediates Inter-Organelle Contacts and Communication that Is Required for Lysosome Activity

“…In general, lysosomes are susceptible to oxidative stress, and lysosome damage by oxidants sensitizes neurons to apoptosis and necrosis [69]. We have previously demonstrated that ROS generation in sel-12 mutants results from increased mitochondrial calcium uptake, which triggers neurodegeneration [17,70]. Here, in sel-12 mutants, we found that mitochondrial ROS plays a role in lysosome enlargement and alkalization (Fig.…”

Modulating mitochondrial calcium channels (TRPM2/MCU/NCX) as a therapeutic strategy for neurodegenerative disorders

“…Characterizing the mitochondrial mechanisms that contribute to neurodegeneration is sorely needed to aid in the identification of potential therapeutic targets. Relieving mitochondrial calcium dysregulation has been approached from multiple angles, such as upregulating calcium-binding proteins Calretinin and Calbindin-D28K to buffer free calcium (La Barbera et al, 2022) as well as targeting pathways such as mTORC1-SKN-1-Nrf (Ryan et al, 2022). Some of the most promising targets for mitoprotection (Figure 1) include NCX and MCU, as well as a channel that has only been found in neuronal mitochondria to aid with zinc (Zn 2+ ) uptake: transient potential melastatin 2 (TRPM2).…”