Interaction of Mitochondrial Calcium and ROS in Neurodegeneration

Abstract

Neurodegenerative disorders are currently incurable devastating diseases which are characterized by the slow and progressive loss of neurons in specific brain regions. Progress in the investigation of the mechanisms of these disorders helped to identify a number of genes associated with familial forms of these diseases and a number of toxins and risk factors which trigger sporadic and toxic forms of these diseases. Recently, some similarities in the mechanisms of neurodegenerative diseases were identified, including the involvement of mitochondria, oxidative stress, and the abnormality of Ca²⁺ signaling in neurons and astrocytes. Thus, mitochondria produce reactive oxygen species during metabolism which play a further role in redox signaling, but this may also act as an additional trigger for abnormal mitochondrial calcium handling, resulting in mitochondrial calcium overload. Combinations of these factors can be the trigger of neuronal cell death in some pathologies. Here, we review the latest literature on the crosstalk of reactive oxygen species and Ca²⁺ in brain mitochondria in physiology and beyond, considering how changes in mitochondrial metabolism or redox signaling can convert this interaction into a pathological event.

Keywords: calcium; cell death; mitochondria; neurodegeneration; neuron; permeability transition pore; reactive oxygen species.

Figure 1

Interaction of calcium and ROS in intracellular signaling. Activation of NADPH oxidase by Ca²⁺ induces ROS production which, in combination with ROS produced in mitochondria or by MAO, can stimulate lipid peroxidation, phospholipase C (PLC) activation, and IP3 production that lead to an additional calcium signal.

Figure 2

ROS and Ca²⁺ in abnormal calcium signaling leading to cell death in Alzheimer’s disease and Parkinson’s disease. Aggregated βAmyloid or α-synucleins form calcium-permeable channels on plasma membrane. PD and AD mutations lead to inhibition of NCLX, massive ROS production, and calcium overload in mitochondria.

Figure 3

Amyotrophic lateral sclerosis: ROS and calcium in neurons. ALS-associated mutations induce mitochondrial dysfunction and decrease antioxidant defense in mitochondria, altering the MEM and mitochondrial calcium handling.