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Disturbances in Mitochondrial Network, Biogenesis, and Mitochondria-Mediated Inflammatory Responses in Selected Brain
Mikołaj Chlubek1, Magdalena Gąssowska-Dobrowolska2, Agnieszka Kolasa3
1Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland.
Insights
Early lead (Pb) exposure disrupts brain mitochondrial biogenesis and dynamics, impairing energy homeostasis and driving neuroinflammation. This study reveals Pb
Area of Science:
- Neuroscience
- Toxicology
- Mitochondrial Biology
Background:
- Lead (Pb) exposure is a known neurotoxicant affecting brain development.
- Mitochondrial dysfunction is implicated in Pb toxicity, but its effects on mitochondrial dynamics and biogenesis during early development are unclear.
Purpose of the Study:
- To investigate the impact of pre- and neonatal Pb exposure on mitochondrial biogenesis and dynamics in the developing rat brain.
- To explore the role of the cGAS-STING pathway in Pb-induced neuroinflammation.
Main Methods:
- Quantification of mRNA and protein levels for mitochondrial fusion/fission regulators and biogenesis markers (qRT-PCR, ELISA).
- Transmission electron microscopy (TEM) for mitochondrial ultrastructure analysis.
- Analysis of mitochondrial electron transport chain (ETC) gene expression and cGAS-STING pathway components.
Main Results:
- Pb exposure reduced PGC-1α and NRF1 levels, suppressed fusion proteins (Mfn1, Mfn2, Opa1), increased Fis1, and depleted Drp1.
- Mitochondrial electron transport chain (ETC) genes were upregulated in a brain-structure-dependent manner, accompanied by morphological abnormalities.
- While cGAS-STING pathway components were upregulated, TBK1 activation was not detected.
Conclusions:
- Early-life Pb exposure disrupts mitochondrial biogenesis and dynamics, impairing brain energy homeostasis.
- Mitochondria are central mediators of Pb-induced neuroinflammation and neurodevelopmental toxicity.
- Low-dose Pb exposure can have significant detrimental effects on brain development.
Abstract:
Lead (Pb) disrupts mitochondrial function, but its impact on the mitochondrial dynamics and biogenesis during early brain development remains insufficiently understood. This study aimed to investigate the effects of pre- and neonatal Pb exposure on the processes involved in mitochondrial network formation in the brains of rat offspring, simulating environmental exposure. We quantified mRNA expression (qRT-PCR) and protein levels (ELISA) of key mitochondrial fusion (Mfn1, Mfn2, Opa1), fission (Drp1, Fis1) regulators, as well as biogenesis markers (PGC-1α, TFAM, NRF1) in the hippocampus, forebrain cortex, and cerebellum of rats exposed to Pb. Mitochondrial ultrastructure was evaluated using transmission electron microscopy (TEM), and the expression of mitochondrial electron transport chain (ETC) genes was analysed (qRT-PCR). Furthermore, to examine the involvement of the cGAS-STING pathway in Pb-induced neuroinflammation, we measured the expression of ISGs (qRT-PCR), TBK1 phosphorylation (Western blot), and 2',3'-cGAMP synthesis (ELISA). Our results showed that Pb exposure markedly reduced PGC-1α and region-specific NRF1 levels, broadly supressed fusion proteins (Mfn1, Mfn2, Opa1), increased Fis1, and depleted Drp1. ETC gene expression (mtNd1, mtCyb and mtCo1) were upregulated in a brain-structure-dependent manner. These molecular changes were accompanied by pronounced mitochondrial morphological abnormalities. Despite upregulation of Mx1, Ifi44, and Sting1, along with synthesis of 2'3'-cGAMP, TBK1 activation was not detected. All these findings demonstrate that early-life Pb exposure, even low-dose, disrupts mitochondrial biogenesis and the fusion-fission machinery, thus impairs brain energy homeostasis, and implicates mitochondria as central mediators of Pb-induced neuroinflammation and neurodevelopmental toxicity.
