The war against Alzheimer, the mitochondrion strikes back!

Mitochondrial Complex I and β-Amyloid Peptide Interplay in Alzheimer’s Disease: A Critical Review of New and Old Little Regarded Findings

“…Wild-type EC slices revealed a marked reduction in oxygen consumption and, in particular, complex-I-related activity was markedly reduced by hAβ1-42 (see Table 1). Furthermore, hAβ1-42 reduced the immunoexpression of both mitochondrial superoxide dismutase (SOD2)-this is consistent with a rapid increase in mitochondrial ROS production induced by hAβ1-42-and cytochrome c, ultimately culminating in oxidative stress and synaptic dysfunction [17,41,240,241].…”

“…Confirmation of this comes from the triple transgenic 3xTg-AD mouse model (human APPSWE, TauP301L, and PS1M146V genes) in which abnormalities in mitochondrial function are seen in the embryonic stage and in young mice long before amyloid accumulation (for ref, see [27]). Starting from the assumption that the Krebs cycle (TCA) and the ETC complexes (I, II, III, and IV) represent the mitochondrial metabolic pathways that respectively provide the reduced substrates and generate the proton gradient across the internal membrane of the mitochondria used to produce energy in the form of ATP, several studies have demonstrated a strong decrease (30-40%) in the activity of complex IV (see [35,36]), as well as in mitochondrial isocitrate dehydrogenase, pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, and the ATP synthase complexes [34,[37][38][39], severely compromising energy metabolism, as demonstrated by the decrease in glucose utilization in the hippocampus, cortex, and posterior cingulate cortex [24,40], and the shortage in mitochondrial ATP production [41,42]. Interestingly, the activities of all these enzymes are inhibited by Aβ [43] providing a possible link between the amyloid cascade and mitochondrial dysfunction in AD.…”

“…In general terms, both proteins (APP and Aβ) present in the mitochondria trigger mitochondrial dysfunction through a series of pathways, such as by interacting with components of the protein import machinery (translocase of the outer membrane-translocase of the inner membrane (TOM-TIM)) [24,134,159], and blocking the mitochondrial translocation of nuclear-encoded proteins [45,[159][160][161][162], like ETC components [93,134,[161][162][163], thus compromising mitochondrial functionality. However, they are also capable of disrupting mitochondrial function in other ways, e.g., directly influencing the activities of ETC complexes, such as cytochrome c oxidase (COX) [134,[164][165][166], complex I [134,140,148], or the F1α subunit of ATP synthase [5,119], thus compromising mitochondrial respiratory function and ATP production [41,54,57,67].…”

mtDNA Maintenance and Alterations in the Pathogenesis of Neurodegenerative Diseases

“…Furthermore, Gonzalez-Hunt, C P et al revealed that the level of mtDNA damage may serve as a powerful and sensitive readout of altered LRRK2 kinase activity in LRRK2 PD [ 210 ]. However, these results have not been replicated in some studies, so further research with a large sample is needed to determine whether mtDNA can be a stable biomarker for investigating the progression of NDDs [ 211 ].…”

Is Mitochondria DNA Variation a Biomarker for AD?

“…However, under a high concentration of ROS, the oxidized mtDNA fragment can be released through large pores in the outer membrane of mitochondria. Released mtDNA may be regarded as a damage-associated molecular pattern (DAMP) or an antigen and induce subsequent inflammatory activation through TNFα, the TLR9/NF-kB signaling pathway or the NLRP3 inflammasome [ 27 , 28 ]. In cybrid cell lines transferred with mtDNA from AD patients, complex IV activity was significantly reduced and ROS production was increased, suggesting the role of mtDNA in the pathology of AD [ 29 ].…”