Insights into Disease-Associated Tau Impact on Mitochondria

Abstract

Abnormal tau protein aggregation in the brain is a hallmark of tauopathies, such as frontotemporal lobar degeneration and Alzheimer's disease. Substantial evidence has been linking tau to neurodegeneration, but the underlying mechanisms have yet to be clearly identified. Mitochondria are paramount organelles in neurons, as they provide the main source of energy (adenosine triphosphate) to these highly energetic cells. Mitochondrial dysfunction was identified as an early event of neurodegenerative diseases occurring even before the cognitive deficits. Tau protein was shown to interact with mitochondrial proteins and to impair mitochondrial bioenergetics and dynamics, leading to neurotoxicity. In this review, we discuss in detail the different impacts of disease-associated tau protein on mitochondrial functions, including mitochondrial transport, network dynamics, mitophagy and bioenergetics. We also give new insights about the effects of abnormal tau protein on mitochondrial neurosteroidogenesis, as well as on the endoplasmic reticulum-mitochondria coupling. A better understanding of the pathomechanisms of abnormal tau-induced mitochondrial failure may help to identify new targets for therapeutic interventions.

Keywords: mitochondria; tau protein; tauopathies.

Figure 1

Schematic representation of oxidative phosphorylation (OXPHOS) in mitochondria. The process of OXPHOS is the main pathway in the cell to produce adenosine triphosphate (ATP). It consists of two coupled processes embedded in the inner mitochondrial membrane (IMM), the electron transport chain (ETC) and the ATP synthesis. In the ETC, the reduced substrates NADH and FADH₂ are oxidized by the NADH-ubiquinone oxidoreductase (Complex I) and succinate-CoenzymeQ reductase (Complex II), respectively. These proteins transfer electrons from their substrates onto Q-10, which serves as a substrate for the CoenzymeQ-cytochrome c oxidoreductase (Complex III). Q-10 is a highly lipophilic substance that is able to diffuse within the IMM. Complex III transfers the electrons from Q-10 onto cytochrome c, which is a water-soluble electron carrier, located at the surface of the IMM in the IMS. In the final step of the ETC, cytochrome c oxidase (Complex IV) uses the electrons from reduced Cyt c to reduce molecular oxygen to water. In the process of transferring electrons, the Complexes I, III and IV actively move protons (H⁺) from the mitochondrial matrix to the IMS, forming the ΔΨm. Ultimately, this potential is used by the ATP synthase (Complex V) to catalyze the generation of ATP from ADP and Pi. ADP: adenosine diphosphate, ATP: adenosine triphosphate, Cyt c: cytochrome c, ETC: electron transport chain, FADH2: flavin adenine dinucleotide, IMM: inner mitochondrial membrane, IMS: intermembrane space, NADH: nicotinamide adenine dinucleotide, Pi: inorganic phosphate, Q-10: coenzymeQ10, ΔΨm: mitochondrial membrane potential.

Figure 2

Schematic illustration of the interplay between mitochondrial biogenesis, fusion, fission, and mitophagy with key proteins involved. Briefly, mitochondrial biogenesis generates functional mitochondria, for instance in response to a reduced mitochondrial mass. The tethering of two mitochondria via the outer mitochondrial membrane (OMM) and IMM mediated through MFN1/ MFN2 and OPA1, respectively, results in their fusion, and thus in the elongation of the mitochondrial network. Contrarily, the recruitment and orchestration of primarily DRP1 and assisting proteins, such as FIS1, causes mitochondrial division. Consequently, the process of mitochondrial fission promotes a more fragmented mitochondrial network and is required for the removal of damaged and dysfunctional mitochondria. Lastly, the accumulation of PINK1 and the subsequent recruitment of Parkin target defective mitochondria that are subsequently degraded by mitophagy. DRP1: dynamin-related protein 1, FIS1: mitochondrial fission protein 1, IMM: inner mitochondrial membrane, MFN1: mitofusin 1, MFN2: mitofusin 2, OMM: outer mitochondrial membrane, OPA1: optic atrophy 1, PINK1: PTEN-induced kinase 1.

Figure 3

Abnormal tau protein impairs mitochondrial function. The scheme summarizes the impact of disease-associated tau protein on the different aspects of mitochondrial function (see details in the text). Of note, the effects illustrated here may be different according to tau models used (phospho-tau versus truncated tau). (1) Abnormal tau inhibits anterograde transport of mitochondria along the axon, leading to a decreased number of mitochondria at the synapse, and mitochondrial perinuclear clustering. (2) Abnormal tau seems to trigger mitochondrial network elongation by increasing MFN2 levels and by triggering DRP1 mislocalization and clustering in actin filaments. (3) Abnormal tau inhibits mitophagy by interacting with Parkin. (4) Abnormal tau disturbs mitochondrial bioenergetics by inhibiting Complex I activity, decreasing the ΔΨm and ATP levels, and increasing ROS production. These effects may also be linked to abnormal tau impacts on the mPTP opening, and/ or to tau direct binding on mitochondrial proteins like voltage-dependent anion channel (VDAC) and subunits on the respiratory Complex V. (5) Abnormal tau disturbs mitochondrial steroidogenesis by decreasing pregnenolone synthesis. Finally, abnormal tau seems to impact on the ER-mitochondrial coupling, which may have consequences on all the above mentioned mitochondrial functions. ANT: adenine nucleotide translocator, ATP: adenosine triphosphate, CI-CV: respiratory complexes I–V, CypD: cyclophilin D, DRP1: dynamin-related protein 1, ER: endoplasmic reticulum, ETC: electron transport chain, GRP75: glucose-related protein 75, IP3R: inositol 3 phosphate receptor, JIP1: c-Jun N-terminal kinase-interacting protein 1, MFN1/ 2: mitofusin 1/ 2, mPTP: mitochondrial permeability transition pore, OPA1: optic atrophy 1, P450scc: cytochrome P450 cholesterol side-chain cleavage enzyme, ROS: reactive oxygen species, TSPO: translocator protein, VDAC: voltage-dependent anion channel, ΔΨm: mitochondrial membrane potential.

Figure 4

Abnormal tau-induced mitochondrial impairments may lead to neuronal death and dementia. Abnormal tau was shown to have a negative impact on all aspects of mitochondrial function (black arrows). These tau-induced disturbances may lead to various neuronal dysfunctions, ranging from subtle alterations in neuronal physiology to cell death and neurodegeneration (red arrows).