Promotion of mitochondrial biogenesis via the regulation of PARIS and PGC-1α by parkin as a mechanism of neuroprotection by carnosic acid

Oct 18, 2020Phytomedicine : international journal of phytotherapy and phytopharmacology

How carnosic acid may protect nerve cells by helping parkin control proteins that increase mitochondria

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Abstract

Carnosic acid (CA) reversed the effects of 6-hydroxydopamine (6-OHDA) on mitochondrial biogenesis-related genes in SH-SY5Y cells.

6-OHDA treatment increased PARIS protein and decreased PGC-1α protein levels, along with reductions in mitochondrial biogenesis-related genes.
CA pretreatment countered the effects of 6-OHDA, restoring levels of PGC-1α and mitochondrial biogenesis-related proteins.
The interaction between PARIS and ubiquitin was enhanced by CA compared to 6-OHDA treatment.
Knockdown of parkin diminished CA's ability to reverse the effects of 6-OHDA on PARIS and PGC-1α expression.
Inhibition of PGC-1α by siRNA blocked CA's protective effects against 6-OHDA-induced mitochondrial biogenesis reduction and apoptosis.

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BACKGROUND: Impairment of mitochondrial biogenesis is associated with the pathological progression of Parkinson's disease (PD). Parkin-interacting substrate (PARIS) can be ubiquitinated by parkin and prevents the repression of proliferator-activated receptor gamma coactivator-1-alpha (PGC-1α).

PURPOSE: This study investigated whether the neuroprotective mechanism of carnosic acid (CA) from rosemary is mediated via the regulation of PARIS and PGC-1α by parkin.

METHODS: The Western blotting and RT-PCR were used to determine protein and mRNA, respectively. To investigate the protein-protein interaction of between PARIS and ubiquitin, the immunoprecipitation assay (IP assay) was utilized. Silencing of endogenous parkin or PGC-1α was performed by using transient transfection of small interfering RNA (siRNA).

RESULTS: SH-SY5Y cells treated with 6-hydroxydopamine (6-OHDA) increased PARIS protein, decreased PGC-1α protein, and reduced protein and mRNA of mitochondrial biogenesis-related genes. CA pretreatment reversed the effects of 6-OHDA. By IP assay, the interaction of PARIS with ubiquitin protein caused by CA was stronger than that caused by 6-OHDA. Moreover, knockdown of parkin attenuated the ability of CA to reverse the 6-OHDA-induced increase in PARIS and decrease in PGC-1α expression. PGC-1α siRNA was used to investigate how CA influenced the effect of 6-OHDA on the modulation of mitochondrial biogenesis and apoptosis. In the presence of PGC-1α siRNA, CA could no longer significantly reverse the reduction of mitochondrial biogenesis or the induction of cleavage of apoptotic-related proteins by 6-OHDA.

CONCLUSION: The cytoprotective of CA is related to the enhancement of mitochondrial biogenesis by inhibiting PARIS and inducing PGC-1α by parkin. The activation of PGC-1α-mediated mitochondrial biogenesis by CA prevents the degeneration of dopaminergic neurons, CA may have therapeutic application in PD.

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Promotion of mitochondrial biogenesis via the regulation of PARIS and PGC-1α by parkin as a mechanism of neuroprotection by carnosic acid

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