Tau accumulation impairs mitophagy via increasing mitochondrial membrane potential and reducing mitochondrial Parkin

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Intracellular accumulation of wild type tau is a hallmark of Alzheimer's disease (AD).
• The precise molecular mechanisms driving tau toxicity remain incompletely understood.
• Mitophagy, the selective degradation of mitochondria, is crucial for cellular health.

Purpose of the Study:

• To investigate the role of wild type tau accumulation in mitophagy deficits in Alzheimer's disease.
• To elucidate the molecular mechanisms by which tau impacts mitochondrial quality control.

Main Methods:

• Quantification of mitophagy markers (COX IV, TOMM20, mtDNA/genomic DNA ratio) in AD brains and tau transgenic mice.
• Overexpression of human wild type tau (htau) in cell lines (HEK293), primary neurons, and mouse brains.
• Assessment of mitochondrial membrane potential, PINK1 and Parkin levels in mitochondrial fractions.
• Analysis of tau protein localization within mitochondrial compartments.

Main Results:

• Mitophagy deficits, indicated by elevated mitophagy markers, were observed in AD brains and htau transgenic mice, correlating with total tau levels.
• Overexpression of htau induced mitophagy deficits in vitro and in vivo.
• Htau overexpression led to increased mitochondrial membrane potential and decreased PINK1/Parkin levels in mitochondria.
• Parkin upregulation mitigated htau-induced mitophagy deficits.
• Tau proteins were found to accumulate in the mitochondrial outer membrane.

Conclusions:

• Intracellular tau accumulation directly impairs mitophagy by inserting into the mitochondrial outer membrane, disrupting mitochondrial membrane potential.
• This disruption impairs the mitochondrial localization of PINK1 and Parkin, key regulators of mitophagy.
• These findings reveal a novel mechanism for tau-induced neuronal toxicity in AD and other tauopathies.