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

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-gamma coactivator-1 alpha (PGC-1 alpha). PGC-1 alpha 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.

Automated summary

Mitochondria play critical roles in neurons by regulating neurotransmission and synaptic plasticity through ATP supply, calcium homeostasis, redox balance control, and apoptosis. Their functional integrity is mainly maintained by mitostasis, involving processes like mitochondrial transport, anchoring, fusion, and fission, regulated by various signaling pathways. The communication between mitochondria and the endoplasmic reticulum (ER) via mitochondria-associated membranes (MAMs) is crucial for Ca2+ buffering. Alterations in mitochondrial activity can lead to increased production of reactive oxygen species, disturbance in physiological metabolism, and mitochondrial dysfunction resulting in cell death through apoptosis.