Mitochondrial DNA Manipulations Affect Tau Oligomerization

Abstract

Background: Mitochondrial dysfunction and tau aggregation occur in Alzheimer’s disease (AD), and exposing cells or rodents to mitochondrial toxins alters their tau. Objective: To further explore how mitochondria influence tau, we measured tau oligomer levels in human neuronal SH-SY5Y cells with different mitochondrial DNA (mtDNA) manipulations. Methods: Specifically, we analyzed cells undergoing ethidium bromide-induced acute mtDNA depletion, ρ0 cells with chronic mtDNA depletion, and cytoplasmic hybrid (cybrid) cell lines containing mtDNA from AD subjects. Results: We found cytochrome oxidase activity was particularly sensitive to acute mtDNA depletion, evidence of metabolic re-programming in the ρ0 cells, and a relatively reduced mtDNA content in cybrids generated through AD subject mitochondrial transfer. In each case tau oligomer levels increased, and acutely depleted and AD cybrid cells also showed a monomer to oligomer shift. Conclusion: We conclude a cell’s mtDNA affects tau oligomerization. Overlapping tau changes across three mtDNA-manipulated models establishes the reproducibility of the phenomenon, and its presence in AD cybrids supports its AD-relevance.

Tau Oligomers Neurotoxicity

“…It has been shown that these changes may result from mtDNA (mitochondrial DNA) disturbances. Cybrid cell lines containing mtDNA from AD patients, as well as cell lines characterized by chronic and acute mtDNA depletion, were found to have higher levels of total tau and TauOs and increased tau phosphorylation on serine 199 [102]. Lowering mtDNA levels can also trigger an adaptive stress response or adaptive metabolic reprogramming.…”

“…Lowering mtDNA levels can also trigger an adaptive stress response or adaptive metabolic reprogramming. For example, Weidling et al [102] showed that cytochrome oxidase (COX) activity is proportional to mtDNA copy number. The authors also showed that dysregulation of the respiratory chain caused by mtDNA disturbances induces the accumulation of TauOs in mitochondria.…”

“…In this study, TauOs were identified with the TOC1 antibody, which binds the unique tau conformation associated with soluble tau dimers and slightly larger oligomers, and the Tau12 antibody, which recognizes a linear epitope in the N-terminal (amino acids 9-18) and detects tau mono-and oligomers. Thus, a study by Weidling et al [102] proved that mitochondrial dysfunction induced by mtDNA abnormalities can both increase TauOs level and facilitate the oligomerization of tau from monomers.…”

Mitochondrial Membrane Potential Influences Aβ Production and Amyloid Precursor Protein localization

“…1A). The ρ0 cells are deviod of detectable mtDNA and have no mitochondrial oxygen consumption as previously described [23]. We examined Aβ secretion from SH-SY5Y control cells and SH-SY5Y ρ0 cells.…”

The Role of Mitonuclear Incompatibility in Bipolar Disorder Susceptibility and Resilience Against Environmental Stressors

“…While the use of human cybrids are commonly used to study mitochondrial dysfunction in neurodegenerative disorders such as Alzheimer's (Onyango et al, 2006;Yu et al, 2016Yu et al, , 2017Weidling et al, 2020), and Parkinson's disease (Keeney et al, 2009;Cronin-Furman et al, 2013;Reeve et al, 2015;Pignataro et al, 2017), there is a paucity of cybrid research in BD and other psychiatric disorders. Munakata et al (2004) reported that the m.3644T > C variant in the mt-ND1 gene was associated with BD and 3644C cybrids exhibited mitochondrial dysfunction including decreases in mitochondrial membrane potential (MMP) and complex I activity compared to 3644T cybrids.…”