A druggable mito-nuclear feedback mechanism that preserves mitochondrial and synaptic function in old-age

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ABSTRACT Mounting evidence suggests mitochondrial decline is an early driver of Alzheimer’s disease and related dementias (ADRD) but the underlying mechanisms remain unclear. Single-cell RNAseq experiments revealed profound differences in the expression of nuclear DNA-encoded mitochondrial genes between neuronal subtypes, suggesting a cell type-specific control of mitochondrial gene expression depending on mitochondrial energy demands. Studying the role of ATP synthase in aging and ADRD, we recently discovered a brain-specific mito-nuclear feedback loop that controls mitochondrial gene expression in response to acetyl-CoA signals from the mitochondria. This mito-nuclear feedback loop is activated by reducing ATP synthase activity, activating AMPK, and subsequently blocking fatty acid synthesis by inhibiting acetyl-CoA carboxylase 1 (ACC1). The block of fatty acid synthesis leads to an accumulation of acetyl-CoA, H3K9 histone acetylation, and increased expression of nuclear-encoded mitochondrial proteins by a mechanism that requires TAF1, the largest component of the transcriptional initiation complex TFIID. Treatment with J147, a partial inhibitor of ATP synthase and an AD drug candidate, increases acetyl-CoA and restores the expression of mitochondrial and synaptic genes, known targets of TAF1. Conducting longitudinal electroencephalogram (EEG) recordings in PS19 mice, an FTD mouse model expressing proteotoxic tau, we observed neuronal hyperexcitability and non-convulsive seizure activity, specifically during slow-wave sleep (SWS). Activation of the mito- nuclear feedback loop by treating the PS19 mice with J147 suppressed the neuronal hyperexcitability and the observed pathological EEG features, revealing that they are likely the consequence of early mitochondrial damage. Here, we hypothesize that age and pathological tau destabilize the mito-nuclear feedback loop by lowering the mitochondrial acetyl-CoA synthesis and export that is required for TAF1 to control synaptic and mitochondrial gene expression. Due to their high mitochondrial energy demands, inhibitory neurons are preferentially susceptible to mito-nuclear insults by tau, resulting in preferential damage to inhibitory neurons. Thus, we further hypothesize that this preferential damage to the mitochondria of inhibitory neurons reduces inhibitory tone and results in early hippocampal hyperexcitability and sleep loss, which can be rescued by treatments that re-activate the mito-nuclear feedback loop.