A New Link to Mitochondrial Impairment in Tauopathies

Abstract

Tauopathies like the "frontotemporal dementia with Parkinsonism linked to chromosome 17" (FTDP-17) are characterized by an aberrant accumulation of intracellular neurofibrillary tangles composed of hyperphosphorylated tau. For FTDP-17, a pathogenic tau mutation P301L was identified. Impaired mitochondrial function including disturbed dynamics such as fission and fusion are most likely major pathomechanisms of most neurodegenerative diseases. However, very little is known if tau itself affects mitochondrial function and dynamics. We addressed this question using SY5Y cells stably overexpressing wild-type (wt) and P301L mutant tau. P301L overexpression resulted in a substantial complex I deficit accompanied by decreased ATP levels and increased susceptibility to oxidative stress. This was paralleled by pronounced changes in mitochondrial morphology, decreased fusion and fission rates accompanied by reduced expression of several fission and fusion factors like OPA-1 or DRP-1. In contrast, overexpression of wt tau exhibits protective effects on mitochondrial function and dynamics including enhanced complex I activity. Our findings clearly link tau bidirectional to mitochondrial function and dynamics, identifying a novel aspect of the physiological role of tau and the pathomechanism of tauopathies.

Genetic Variation of <b><i>MT-ND</i></b> Genes in Frontotemporal Lobar Degeneration: Biochemical Phenotype-Genotype Correlation

“…This can suggest that a decrease in complex I activity may be involved in the pathogenesis of the disease. These results are in agreement with previous studies that have also demonstrated mitochondrial impairment activity in related diseases, such as AD, PD, ALS and tauopathies [32,85,86,87,88]. Moreover, our group has previously reported a complex I deficiency in a patient with FTLD [22].…”

Mitochondrial hyperpolarization in iPSC-derived neurons from patients of FTDP-17 with 10+16 MAPT mutation leads to oxidative stress and neurodegeneration

“…Mitochondrial dysfunction is a common pathological feature of neurodegenerative disorders and is often characterized by a decrease in the mitochondrial membrane potential [9], which has also been observed in different models of tauopathies [6], [36]. Here, we show that despite their reduced mitochondrial respiration, the iPSC-derived neurons from the patients carrying the 10+16 MAPT mutation present an increase in the mitochondrial membrane potential that is partially maintained by the complex V working in reverse mode: pumping protons to the intermembrane space at the expense of ATP hydrolysis.…”

Connecting the dots between tau dysfunction and neurodegeneration

“…Consistent with these findings, tau transgenic flies and mice have significantly elongated mitochondria [47], and tau transgenic mice have reduced mitochondrial complex I and V activity and other mitochondrial respiratory defects [51]. Studies in cell culture further support a role for structural and functional disturbances in mitochondria, as tau expression in neuroblastoma cells causes impaired mitochondrial fission and fusion, reduced mitochondrial complex I activity and reduced ATP levels [52]. …”