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.

Role of the Lipid Membrane and Membrane Proteins in Tau Pathology

“…Wang et al (2009) showed that when K18 tau with the K280 mutant (Tau RD K) is expressed in N2a cells, Tau RD K interacts with LAMP-2A in lysosome and is thereby processed to highly amyloidogenic fragments which nucleate aggregation of tau. Growing evidence suggests that mitochondrial dysfunction is closely related to the pathophysiology of tauopathies (Szabo et al, 2020;Wang et al, 2020). Phosphorylated tau is also found at the mitochondria membrane (Jancsik et al, 1989;Rendon et al, 1990).…”

Mitochondrial links between brain aging and Alzheimer’s disease

“…Several studies have reported that amyloid precursor protein (APP) and Aβ localize to mitochondria, and Aβ appears to act as a mitochondrial toxin [78][79][80][81][82][83][84][85]. The tau protein also appears to localize to mitochondria and contribute to mitochondrial dysfunction through multiple mechanisms [86][87][88][89][90][91][92]. Similarly, a cleavage product from the apolipoprotein E protein displays a mitochondrial localization signal, targets mitochondria, and inhibits COX activity [93,94].…”

Advances in the Relationship between Tau Protein and Morphine De-pendence in Cognitive Dysfunction

“…tive damage to the central nervous system. The results showed that the expression of human tau protein could cause the dynamic imbalance of mitochondrial division and fusion between HEK293 cells and primary neurons, and the neuronal process was significantly shortened and the cell viability decreased [24] . Damage to mitochondrial function can affect mitochondrial endoplasmic reticulum…”