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Restoration of Miro1's N-terminal GTPase function alleviates prenatal stress-induced mitochondrial fission via Drp1
Gee Euhn Choi1,2, Ji Yong Park3, Mo Ran Park3
1Laboratory of Veterinary Biochemistry, College of Veterinary Medicine and Veterinary Medical Research Institute, Jeju National University, Jeju, 63243, South Korea.
Insights
Prenatal stress impairs mitochondrial dynamics in developing neurons by downregulating Miro1, leading to behavioral deficits. Restoring Miro1 function can rescue these impairments.
Area of Science:
- Neuroscience
- Cell Biology
- Developmental Biology
Background:
- Prenatal stress exposure negatively impacts offspring neurodevelopment, causing behavioral and neuropsychiatric disorders.
- Mitochondrial dynamics, including transport and morphology, are crucial for neuronal development and function.
- Understanding the molecular regulators of mitochondrial dynamics is essential for preventing prenatal stress-induced impairments.
Purpose of the Study:
- To investigate the interplay between mitochondrial transport and fusion/fission in differentiating neurons under prenatal stress.
- To identify the key molecular regulator modulating mitochondrial dynamics during prenatal stress exposure.
- To explore the therapeutic potential of targeting mitochondrial dynamics for preventing stress-induced neurodevelopmental deficits.
Main Methods:
- Utilized primary hippocampal neurons from mice and human induced-pluripotent stem cell (hiPSC)-derived neurons exposed to prenatal stress.
- Employed adeno-associated virus (AAV) vectors in mouse models to manipulate protein expression in hippocampal regions.
- Assessed mitochondrial dynamics, protein expression levels (Miro1, Drp1), phosphorylation, and ER-mitochondria contact (ERMC) formation.
Main Results:
- Prenatal glucocorticoids induced mitochondrial motility arrest and fragmentation in differentiating neurons.
- Glucocorticoid exposure downregulated Miro1 and increased Drp1 phosphorylation (Ser616), disrupting mitochondrial dynamics.
- Miro1 overexpression restored mitochondrial motility and ERMC formation, decreasing Drp1 phosphorylation and rescuing behavioral deficits in offspring.
Conclusions:
- Prenatal glucocorticoid exposure downregulates Miro1, leading to mitochondrial dysfunction via Drp1 phosphorylation (Ser616) in differentiating neurons.
- The N-terminal GTPase domain of Miro1 is critical for ERMC formation and mitigating stress-induced mitochondrial defects.
- Targeting Miro1 offers a potential therapeutic strategy for preventing prenatal stress-induced neurodevelopmental and behavioral disorders.
Background:
Prenatal stress exposure irreversibly impairs mitochondrial dynamics, including mitochondrial trafficking and morphology in offspring, leading to neurodevelopmental and neuropsychiatric disorders in adulthood. Thus, understanding the molecular mechanism controlling mitochondrial dynamics in differentiating neurons is crucial to prevent the prenatal stress-induced impairments in behavior. We investigated the interplay between mitochondrial transport and fusion/fission in differentiating neurons exposed to prenatal stress, leading to ensuing behavior impairments, and then tried to identify the primary regulator that modulates both phenomena.
Methods:
We used primary hippocampal neurons of mice exposed to prenatal stress and human induced-pluripotent stem cell (hiPSC)-derived neurons, for investigating the impact of glucocorticoid on mitochondrial dynamics during differentiation. For constructing mouse models, we used AAV vectors into mouse pups exposed to prenatal stress to regulate protein expressions in hippocampal regions.
Results:
We first observed that prenatal exposure to glucocorticoids induced motility arrest and fragmentation of mitochondria in differentiating neurons derived from mouse fetuses (E18) and human induced pluripotent stem cells (hiPSCs). Further, glucocorticoid exposure during neurogenesis selectively downregulated Miro1 and increased Drp1 phosphorylation (Ser616). MIRO1 overexpression restored mitochondrial motility and increased intramitochondrial calcium influx through ER-mitochondria contact (ERMC) formation. Furthermore, we determined that the N-terminal GTPase domain of Miro1 plays a critical role in ERMC formation, which then decreased Drp1 phosphorylation (Ser616). Similarly, prenatal corticosterone exposure led to impaired neuropsychiatric and cognitive function in the offspring by affecting mitochondrial distribution and synaptogenesis, rescued by Miro1WT, but not N-terminal GTPase active form Miro1P26V, expression.
Conclusion:
Prenatal glucocorticoid-mediated Miro1 downregulation contributes to dysfunction in mitochondrial dynamics through Drp1 phosphorylation (Ser616) in differentiating neurons.
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