Mitostasis, Calcium and Free Radicals in Health, Aging and Neurodegeneration

Abstract

Mitochondria play key roles in ATP supply, calcium homeostasis, redox balance control and apoptosis, which in neurons are fundamental for neurotransmission and to allow synaptic plasticity. Their functional integrity is maintained by mitostasis, a process that involves mitochondrial transport, anchoring, fusion and fission processes regulated by different signaling pathways but mainly by the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). PGC-1α also favors Ca2+ homeostasis, reduces oxidative stress, modulates inflammatory processes and mobilizes mitochondria to where they are needed. To achieve their functions, mitochondria are tightly connected to the endoplasmic reticulum (ER) through specialized structures of the ER termed mitochondria-associated membranes (MAMs), which facilitate the communication between these two organelles mainly to aim Ca2+ buffering. Alterations in mitochondrial activity enhance reactive oxygen species (ROS) production, disturbing the physiological metabolism and causing cell damage. Furthermore, cytosolic Ca2+ overload results in an increase in mitochondrial Ca2+, resulting in mitochondrial dysfunction and the induction of mitochondrial permeability transition pore (mPTP) opening, leading to mitochondrial swelling and cell death through apoptosis as demonstrated in several neuropathologies. In summary, mitochondrial homeostasis is critical to maintain neuronal function; in fact, their regulation aims to improve neuronal viability and to protect against aging and neurodegenerative diseases.

Early mitochondrial stress and metabolic imbalance lead to photoreceptor cell death in retinal degeneration

“…Our findings provide a plausible framework for the etiology of retinal degeneration by incorporating unique photoreceptor 'omics' and physiology in concert with our observations from the rd1 mutant retina. In addition, our studies are consistent with the mechanistic underpinning of neurodegenerative diseases 62,63 and should have broad implications for deciphering molecular and cellular drivers of disease pathology. Discovery of metabolic and signaling pathways that are altered in anticipation of disease sets the foundation for drug discovery and interventions at an early stage, thereby improving outcomes in clinical management.…”

The Difference Between The Response To Glutamate Excitotoxicity and The Role Of Ca2+ Channel Blockers in Cortical Neuron and SH-SY5Y Cells Cultures

“…Numerous studies highlight the important role of VGCC blockers to treat glutamate excitotoxicity (Godoy et al, 2021;Higley & Sabatini, 2012;Kim et al, 2016;Zyśk et al, 2018). In the light of the results summarized in the literature, N-type blockers are known to have protective effects toxicity of NMDAR-mediated Ca 2+ entry (Kimura et al, 1999;Vallazza-Deschamps et al, 2005).…”

“…Ca 2+ homeostasis is essential for the survival of neurons, on the other hand increased intracellular Ca 2+ concentration disrupts calcium homeostasis, and free oxygen radicals formation which could degenerate neurons and synaptic loss (Godoy et al, 2021) (5). For this reason, blocking excitotoxicity through inhibition of VGCC activity in neurons are an especially appealing point for neuroprotection (Godoy et al, 2021;Higley & Sabatini, 2012;Kim et al, 2016). By contrast to neuroprotective effects of P/Q-type and N-type calcium channel blockers, there is a gap for L-type calcium channels blockers in relation to glutamate excitotoxicity (Vallazza-Deschamps et al, 2005;Wheeler et al, 1996).…”

Insight into the mitochondrial unfolded protein response and cancer: opportunities and challenges

“…Previous studies have shown that the decline in brain metabolic activity during aging is associated with mitochondrial dysfunction. Disorders of OXPHOS, imbalanced Ca 2+ buffering, and dysregulation of UPR mt -related proteins lead to neuronal decline during aging [ 71 ]. Under ER stress, Ca 2+ is transported to mitochondria through the MAM, which ultimately leads to increased expression of the mitochondrial protease LONP1 [ 72 , 73 ].…”