Inhibiting mitochondrial excessive fission alleviates the neuronal damage in Parkinson's disease via regulating PGC-1α mediated mitochondrial biogenesis

May 4, 2025Experimental neurology

Reducing mitochondrial splitting may protect brain cells in Parkinson's disease by boosting mitochondrial growth through PGC-1α

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Abstract

Inhibition of mitochondrial excessive fission by Mdivi-1 led to increased expression of PGC-1α and related factors.

Inhibiting mitochondrial excessive fission is associated with increased nuclear translocation of PGC-1α.
Elevated PGC-1α levels promote the expression of downstream factors NRF1/2 and TFAM, enhancing mitochondrial biogenesis.
Alleviation of dopaminergic synaptic injury and neuronal apoptosis was observed alongside improvements in motor function.
Inhibition of PGC-1α reduced the beneficial effects of fission inhibition in both in-vitro and in-vivo models.
Activation of the CaMKII/CREB pathway is linked to the enhanced expression of PGC-1α, NRF1, and TFAM.
Inhibition of mitochondrial excessive fission also activates the AMPK/Sirt1 pathway, leading to post-translational modifications of PGC-1α.

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Mitochondrial excessive fission is one of representative pathological features and a principal element triggering the neuronal damage in Parkinson's disease (PD). Inhibiting mitochondrial excessive fission benefits the pathology of PD through promoting mitochondrial biogenesis, but the detailed mechanism has not been clarified. In our study, we revealed that inhibiting mitochondrial excessive fission by Mdivi-1, the dynamin related protein 1 (DRP1) inhibitor, increased the expression and nuclear translocation of peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α), as well as its downstream transcriptional factors, nuclear respiratory factor 1/2 (NRF1/2) and mitochondrial transcription factor A (TFAM), and therefore promoted mitochondrial biogenesis. Suppression of mitochondrial excessive fission alleviated dopaminergic synaptic injury, neuronal apoptosis and motor dysfunction, while inhibiting PGC-1α attenuated these ameliorative effects in both in-vitro and in-vivo PD models. Mechanistic study showed that inhibiting mitochondrial excessive fission facilitated the expression of PGC-1α, NRF1 and TFAM by activation of Ca/calmodulin-dependent serine/threonine kinase II (CaMKII)/cAMP-response element binding protein (CREB) pathway. Inhibiting mitochondrial excessive fission also activated AMP-activated serine/threonine kinase (AMPK)/Sirtuin1 (Sirt1) pathway, and then phosphorylated and deacetylated PGC-1α by post-translational modifications. In conclusion, inhibiting mitochondrial excessive fission could promote mitochondrial biogenesis through activation of PGC-1α and therefore rescue the impaired dopaminergic neurons, which provided evidence for targeting mitochondrial excessive fission for the treatment of PD and new drug developments. 2+

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