Moosmann, B. | bioRxiv Science

bioRxiv2023

Adaptive epigenetic regulation of neuronal metabolism by a mitochondrial redox signal

Different signaling pathways connect the mitochondrion with the transcriptional machinery in the nucleus. Redox events are thought to play a substantial role along this axis, however, many open questions about their specificity, quantitative importance and mode of action remain. Here, we have employed subtoxic doses of the complex I inhibitor MPP+ in human neuronal LUHMES cells to characterize the contribution of scavengeable redox signals to mito-nuclear communication. MPP+ evoked a broadly targeted transcriptional induction of nuclear-encoded respiratory chain complex (RCC) subunits. Nanomolar doses of phenothiazine (PHT), a mitochondrially active antioxidant, attenuated these transcriptional effects by approximately half, but did not modulate the bioenergetic markers ATP, NAD+, NADH, lactate, or glucose. Transcriptional induction by MPP+ was accompanied by a loss of nuclear 5-methyl-cytosine and an increase in histone H3K14 acetylation, both of which were entirely prevented by PHT. Inhibitor and PHT reversibility experiments suggested that these alterations were mediated by lowered DNMT3B and SIRT1 levels, respectively. Analysis of MPTP-treated mice recapitulated the PHT-reversible induction of histone acetylation and DNMT3B suppression in vivo. Moreover, PHT completely abrogated the statistical significance of the association of MPP+ with the selective induction of mitochondrially imported proteins and RCC subunits. We conclude that the mitochondrion employs a redox signal to announce impending, but not yet acute mitochondrial distress to the nucleus, in order to selectively upregulate mito-metabolic genes via chromatin reorganization. Our results have implications for the interpretation of the observed epigenetic changes in Parkinsons disease and other neurodegenerative disorders.

cell biology↗

bioRxiv2018

The pathological hallmarks of Alzheimer’s disease derive from compensatory responses to NMDA receptor insufficiency

Alzheimers disease is characterized by intracellular aggregates of hyperphosphorylated tau protein and extracellular plaques of amyloid {beta} peptide, a product of APP processing. The origin of these pathological hallmarks has remained elusive. Here, we have tested the idea that both alterations, at the onset of the disease, may constitute compensatory responses to the same causative and initial trigger, namely NMDA receptor insufficiency. Treatment of rat cortical neurons with the specific NMDA receptor antagonist AP5 within 4 h caused a significant increase in tau phosphorylation at the AT8 and S404 epitopes as well as an increase in APP expression and A{beta} 40 secretion. Single intraperitoneal injections of the NMDA receptor open channel blocker MK-801 into wild-type mice reproduced all of these changes in a brain region-specific fashion either at latency 4 h or 24 h. Subchronic treatment with MK-801 for 6 weeks induced AT8, S404 and S396 immunoreactivity selectively in female mice. We conclude that the pivotal pathological alterations in Alzheimers disease represent runaway physiological responses to persistently insufficient excitatory neurotransmission. In view of the evidence for excitatory insufficiency in trisomy 21 patients, PS1 mutation carriers and ApoE4 carriers, our data suggest a common pathomechanism behind familial, sporadic, and risk allele-triggered Alzheimers disease. The potential of this mechanism to reconcile previous conflicting observations is discussed.

neuroscience↗