Several pathophysiological factors are implicated in neurodegeneration, including but not limited to protein misfolding, dysfunction and aggregation of the proteasome, mutations of molecular chaperones, oxidative stress and formation of free radicals or reactive oxygen species (ROS), mitochondrial dysfunction, and neuroinflammation. Mitochondria are involved in the maintenance of calcium homeostasis, inorganic cofactor iron-sulfur clusters, ROS generation, and signaling and metabolism of lipids, in close association with the endoplasmic reticulum. Moreover, they are a primary contributor to amyloid and tau deposition in brain tissue in Alzheimer’s disease. Dopaminergic neurons, cholinergic receptors, and numerous structures involved in neurodegeneration are prone to oxidative stress, which invokes a cascade of events, including mitochondrial dysfunction and neuroinflammation. Therefore, the impairment of nuclear and mtDNA contributes to the degradation of neurons and subsequent clinical effects.

Many correlated or uncorrelated factors can disturb mitochondrial morphology and alter mitochondrial dynamics, resulting in electrophysiology problems correlated with neurodegenerative disorders. Continuous changes by fission and fusion events can lead to an irreversible loss of internal mitochondrial structural features, limiting the internal area and energy and promoting apoptosis. In deficient infusion cells, the large mesh of interconnected mitochondria prohibits efficient mitochondrial motility in small pathways like neuronal processes. However, the cause of this decreased mitochondrial motility in fusion deficient cells is not very clear. Additionally, mtDNA accumulates mutations at a much higher rate than nuclear DNA, mostly because of higher replication rates and less efficient repair mechanisms, leading to the formation of SNPs. Comparative analysis of very large worldwide mtDNA SNP datasets has led to the classification of human mtDNA into certain groupings known as mtDNA haplogroups, reflecting maternal ancestral lineages with specific phylogeographic distributions. Significant effort has been put into connecting mtDNA haplogroups with the risk of neurodegeneration.

Limitations in mitochondrial bioenergetics and oxidative phosphorylation are often associated with increased free radical production and consequently oxidative damage that may contribute to neurodegenerative diseases. Therefore, this Special Issue aims to collate innovative original research and review articles that reveal pathogenic pathways and potential therapeutic targets, presenting the crosstalk between oxidative stress and mitochondrial dynamics.

Potential topics include but are not limited to the following:

• Evidence of mitochondrial dysfunction and regional alterations of brain metabolism and their relation to other somatic symptoms
• Mitochondrial dynamics in neurodegeneration
• Methods, protocols, and computational tools for mitochondrial testing in neurodegeneration
• Novel therapies addressing mitochondrial dysfunction and oxidative stress
• Signs and lesions of mitochondrial dysfunctionalities in early or moderate mild cognitive impairment (MCI)
• SNP formation and mtDNA haplogroups