Mitochondria and Calcium in Alzheimer’s Disease: From Cell Signaling to Neuronal Cell Death

Ca2+ levels are tightly regulated in mitochondria. If excessive Ca2+ levels are reached within mitochondria, then key mitochondrial functions are impaired, leading to enhanced generation of reactive oxygen species and activation of apoptosis, processes that take place in AD. The combination of different technologies, such as RNA-seq, targeted fluorescent probes, multiphoton microscopy, and transgenic mouse models of AD, has made it possible to understand the underlying mechanisms of mitochondrial Ca2+ dysregulation and its contribution to a more general Ca2+ impairment in AD. Aβ causes cytosolic and mitochondrial Ca2+ overload both in vitro and in vivo. Misfolded and hyperphosphorylated tau protein also disrupts Ca2+ homeostasis in mitochondria. Identifying targets to maintain mitochondrial Ca2+ homeostasis and correct mitochondrial function, particularly mitochondrial Ca2+ transporters, could offer promising venues for the development of drugs against AD. Mitochondrial dysfunction has been implicated in the pathogenesis of almost all neurological diseases, including Alzheimer’s disease (AD). Historically, a primary focus in this context has been the link between mitochondrial dynamics and amyloid β toxicity. Recent evidence suggests that dysregulation of mitochondrial calcium homeostasis is also related to tau and other risk factors in AD, although an ongoing challenge in the field is that data collected from different models or experimental settings have not always been consistent. We examine recent literature on mitochondrial dysregulation in AD, with special emphasis on mitochondrial calcium. We include data from in vitro systems, genetic animal models, and AD-derived human tissue, and discuss whether mitochondrial calcium transporters should be proposed as therapeutic candidates for the development of neuroprotective drugs against AD. Mitochondrial dysfunction has been implicated in the pathogenesis of almost all neurological diseases, including Alzheimer’s disease (AD). Historically, a primary focus in this context has been the link between mitochondrial dynamics and amyloid β toxicity. Recent evidence suggests that dysregulation of mitochondrial calcium homeostasis is also related to tau and other risk factors in AD, although an ongoing challenge in the field is that data collected from different models or experimental settings have not always been consistent. We examine recent literature on mitochondrial dysregulation in AD, with special emphasis on mitochondrial calcium. We include data from in vitro systems, genetic animal models, and AD-derived human tissue, and discuss whether mitochondrial calcium transporters should be proposed as therapeutic candidates for the development of neuroprotective drugs against AD. a peptide of 38–43 amino acids that is the main component of amyloid plaques. Aβ1–42 is more hydrophobic and prone to aggregation, and is the most predominant peptide in amyloid plaques. It has been proposed that soluble Aβ oligomers (Aβo), rather than amyloid plaques, are the most neurotoxic species of Aβ. subcellular regions of localized high Ca2+ concentration that are key elements of Ca2+ signaling, particularly in neurons and cardiac cells. They are formed at sites where Ca2+ enters the cytoplasm through Ca2+ channels either in the plasma membrane or in internal stores such that, when the channel opens, Ca2+ concentration increases up to several hundred micromolar. They can be visualized using fluorescence/bioluminescence reporters such as aequorins. AD caused by mutations in the genes encoding amyloid precursor protein (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2). These mutations are extremely rare (<1% of people with AD carry one of these mutations), and result in early-onset symptoms of disease (in people as young as 45 years of age). the most common form of AD. It is detectable in people aged 65 years and older. Little is known about the cause of the onset of sAD, but is likely a combination of genetic risk factors, diet, and environment. the main mitochondrial pathway for Ca2+ uptake. It constitutes a macromolecular complex of proteins (named the mitochondrial calcium uniporter complex), including the pore and several regulatory subunits. The MCU defines the pore domain of the complex. the gatekeepers of MCU. MICU1 and MICU2 are Ca2+ sensors (given their two Ca2+-binding EF-hand motifs). The combination of the two regulates the MCU complex to prevent Ca2+ overload at low extramitochondrial Ca2+ concentrations. MICU3, mainly expressed in the CNS, enhances mitochondrial Ca2+ uptake in neurons. the driving force for cytosolic Ca2+ to accumulate in the mitochondrial matrix via the MCU. It is generated by proton pumps in the electronic transport chain and is negative inside mitochondria. a megachannel that allows the efflux of metabolites with a molecular weight of up to 1.5 kDa from the mitochondrial matrix. It is activated by multiple effectors, especially Ca2+ in the presence of phosphate and reactive oxygen species (ROS). The mPTP is mainly formed by ATP synthase and is regulated by cyclophilin D (CypD). Its inhibition by cyclosporine A (CsA) leads to closure of the pore. the major pathway for Ca2+ efflux from the mitochondrial matrix. Ca2+ extrusion is coupled to Na+ influx from the cytosol into the mitochondrial matrix; however, Na+ can be effectively replaced by Li+ (and hence its name). an integral membrane protein located in the endoplasmic reticulum (ER). In the brain, neurons mainly contain PSEN1 and PSEN2. They participate in Aβ generation as catalytic enzymes within the γ-secretase complex. a protein contained within the axons of nerve cells that promotes the assembly and stabilization of microtubules, the main components of the cytoskeleton and key players in the transport of vesicles, organelles, and proteins. Hyperphosphorylation of tau results in misfolding and the formation of neurofibrillary tangles. the most abundant channel in the outer mitochondrial membrane (OMM) that provides an aqueous pathway from the cytosol and across the OMM. It allows the entry of substrates for mitochondria to produce ATP, such as pyruvate, succinate, and NADH, as well as Ca2+, Na+, and K+.