Corrupted ER‐mitochondrial calcium homeostasis promotes the collapse of proteostasis

Abstract

Aging and age-related diseases are associated with a decline of protein homeostasis (proteostasis), but the mechanisms underlying this decline are not clear. In particular, decreased proteostasis is a widespread molecular feature of neurodegenerative diseases, such as Alzheimer's disease (AD). Familial AD is largely caused by mutations in the presenilin encoding genes; however, their role in AD is not understood. In this study, we investigate the role of presenilins in proteostasis using the model system Caenorhabditis elegans. Previously, we found that mutations in C. elegans presenilin cause elevated ER to mitochondria calcium signaling, which leads to an increase in mitochondrial generated oxidative stress. This, in turn, promotes neurodegeneration.To understand the cellular mechanisms driving neurodegeneration, using several molecular readouts of protein stability in C. elegans, we find that presenilin mutants have widespread defects in proteostasis. Markedly, we demonstrate that these defects are independent of the protease activity of presenilin and that reduction in ER to mitochondrial calcium signaling can significantly prevent the proteostasis defects observed in presenilin mutants. Furthermore, we show that supplementing presenilin mutants with antioxidants suppresses the proteostasis defects. Our findings indicate that defective ER to mitochondria calcium signaling promotes proteostatic collapse in presenilin mutants by increasing oxidative stress.

Increased Mitochondrial Calcium Uptake and Concomitant Hyperactivity by Presenilin Loss Promotes mTORC1 Signaling to Drive Neurodegeneration

“…1A-B), thus, indicating typical proteasomal degradation of the ub(G76V) tagged GFP. These data are consistent with normal proteasome activity of sel-12 mutants previously reported (16).…”

“…Therefore, they cannot use cell division to dilute damage organelles or protein aggregates and, hence, depend on e cient proteostatic pathways to clear faulty proteins and organelles. From our investigations, we have found that mutations in the C. elegans presenilin ortholog, SEL-12, similar to mutations in human presenilin, results in altered ER calcium signaling, ER-mitochondrial communication and mitochondrial function (5,12,(16)(17)(18)(19)(20)(21)(22). In sel-12 mutants, neuronal mitochondrial calcium levels are elevated, which results in mitochondrial hyperactivity and an increase reactive oxygen species (ROS) production.…”

“…Importantly, reduction of ER calcium release or mitochondrial calcium uptake rescues neuronal as well as mitochondrial function and prevents the neurodegenerative phenotypes observed in sel-12 mutants (23). Additionally, this altered ER-mitochondrial calcium signaling and mitochondrial hyperactivity leads to profound defects in proteostasis and has been found to be independent of gammasecretase activity (16). Furthermore, examining cells from AD patients with PSEN1 mutations, others and we have found that mitochondrial hyperactivity promotes elevated ROS production that can be prevented by blocking mitochondrial calcium uptake (18,23).…”

Interrelation between ROS and Ca2+ in aging and age-related diseases

“…For instance, aged rat neurons exhibit increased cytosolic resting Ca 2+ levels, enhanced Ca 2+ release from the endoplasmic reticulum (ER), elevated Ca 2+ flux between ER and mitochondria and changed expression pattern of key proteins involved in cellular Ca 2+ homeostasis [ 17 ]. Experiments in C. elegans revealed that a defected ER to mitochondrial Ca 2+ signaling resulted in increased mitochondrial Ca 2+ levels, causing oxidative stress and proteostatic collapse [ 18 ]. Furthermore, enhanced inter-compartmental Ca 2+ flux between ER and mitochondria due to closer proximity between these organelles was found to modulate mitochondrial metabolism and apoptotic threshold in aged endothelial cells [ 19 ].…”

The Role of Ca2+ Signaling in Aging and Neurodegeneration: Insights from Caenorhabditis elegans Models

“…[18]. Moreover, sel-12 mutants show a proteostasis defect that leads to a premature protein aggregation in C. elegans models of polyglutamine, Aβ or mutant tau expression; this effect was suppressed by knocking down the IP 3 R with itr-1 RNAi, in calreticulin (crt-1) mutants, or in mcu-1 mutants [77]. These results suggest that the presenilin orthologue sel-12 has a critical role regulating ER to mitochondria Ca 2+ transfer, and sel-12 mutations produce an increase of this Ca 2+ transfer that plays a key role in the development of mitochondrial dysfunction, proteostasis, and neurodegeneration.…”