Sterben, S. P. | Search bioRxiv

bioRxiv2025

Microglia Mitochondria Drive Neuronal Maturation via Metabolic and Transcriptional Reprogramming

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by impaired social interactions, repetitive behaviors, and disrupted neuronal circuit maturation. Emerging evidence implicates both microglial function and mitochondrial regulation as critical determinants of ASD pathogenesis. Here, we identified microglia and their mitochondria as active modulators of neuronal circuit development, highlighting their potential roles as mechanistic contributors and biomarkers in ASD progression. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=147 SRC="FIGDIR/small/651306v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@6794ddorg.highwire.dtl.DTLVardef@5e71cborg.highwire.dtl.DTLVardef@80f0acorg.highwire.dtl.DTLVardef@138c828_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2025

The Silent Saboteur: How Mitochondria Shape the Long-Term Fate of the Injured Brain.

Traumatic brain injury (TBI) is a major risk factor for neurodegenerative diseases, including Alzheimers disease (AD), yet the mechanistic link remains unclear. Here, we integrated human patient-derived transcriptomics with a 3D in vitro brain injury model to dissect cell-specific mitochondrial dysfunction as a driver of injury-induced neurodegeneration. Comparative transcriptomic analysis at 6 and 48 hours post-injury revealed conserved mitochondrial impairments across excitatory neurons, interneurons, astrocytes, and microglia. Using a novel cell-specific mitochondria tracking system, we demonstrate prolonged neuronal mitochondrial fragmentation, bioenergetic failure, and metabolic instability, coinciding with the emergence of AD markers, including pTau, APP, and A{beta}42/40 dysregulation. Glial mitochondria exhibited delayed but distinct metabolic dysfunctions, with astrocytes impaired metabolic support and microglia sustained chronic inflammation. These findings establish neuronal mitochondrial failure as an early trigger of injury-induced neurodegeneration, reinforcing mitochondrial dysfunction as a therapeutic target for preventing TBI-driven AD pathology.

neuroscience↗