Overexpression of PGC-1α influences the mitochondrial unfolded protein response (mtUPR) induced by MPP+ in human SH-SY5Y neuroblastoma cells

Abstract

Parkinson's disease (PD) is a common dyskinesia disease, the mitochondrial unfolded protein response (mtUPR) may be directly or indirectly involved in the occurrence and development of PD, although the exact mechanism is unclear. We established a dopaminergic neuronal-like cell model of PD, by overexpression of PGC-1α to detect evaluate the expression of proteases and molecular chaperones of involved in the mtUPR, as well as the expression of PGC-1α and LRPPRC, illustrated the distribution of LRPPRC. Remarkably, the mtUPR activation reached maximal at 24 h after MPP + treatment in SH-SY5Y cells, which the protein and transcription levels of the proteases and molecular chaperones reached maximal. The proteases and molecular chaperones were significantly increased when overexpressed PGC-1α, which indicated that PGC-1α overexpression activated the mtUPR, and PGC-1α had a protective effect on SH-SY5Y cells. The expression levels of PGC-1α and LRPPRC were significantly improved in the PGC-1α overexpression groups. LRPPRC was markedly reduced in the nucleus, suggesting that PGC-1α overexpression may play a protective role to the mitochondria through LRPPRC. Our finding indicates that overexpression of PGC-1α may activate mtUPR, reducing the oxidative stress injury induced by MPP + through LRPPRC signaling, thus maintain mitochondrial homeostasis. Parkinson's disease (PD) is a common neurodegenerative disease characterized by the formation of Lewy bodies and the degeneration of dopaminergic neurons in the dense parts of the substantia nigra (SN) and striatum 1. At present, the pathogenesis of PD remains unclear. Nonetheless, mitochondrial dysfunction is closely associated with protein quality control (PQC) 2 , and PQC disorder plays a very important role in the pathogenesis of PD 3. Mitochondrial protein quality control (mtPQC) is the principal mechanism that maintainscell homeostasis. Among the pathways triggered by stress, the mitochondrial unfolded protein response (mtUPR) acts to restore proteostasis specifically within the mitochondria. The mtUPR reacts to mitochondrial proteotoxic stresses, such as the accumulation of unfolded or misfolded proteins, leading to upregulated expression of mitochondrial molecular chaperones (such as the heat shock proteins (HSPs) HSPE1, HSP60 and HSPA9) and proteases (such as CLPP, Lon, YME1L1, afg3l2 and SPG7) encoded by nuclear genes 4-7. The mtUPR assists newly synthesized proteins folding correctly and it helps in the repair of misfolded or aggregated proteins, and the proteolytic removal of irreversibly damaged protein. Thus, the mtUPR is a mitochondrial-to-nuclear retrograde signal transduction pathway 8 that ensures the quality of the mitochondrial proteome. Many factors and various compounds can induce the mtUPR. Paraquat (an herbicide) and rotenone (a pesticide) are common toxins that trigger the mammalian mtUPR by inducing mitochondrial dysfunction 9-11 , both of

Dysregulation of PGC-1α-Dependent Transcriptional Programs in Neurological and Developmental Disorders: Therapeutic Challenges and Opportunities

“…Additionally, a loss of PGC-1α significantly exacerbates cell death in MPTP [ 52 , 210 , 211 , 212 , 213 , 214 ] and α-synuclein-induced cell death [ 192 , 215 , 216 ] models of PD, while overexpression of PGC-1α enhances autophagy and reduces rotenone- and α-synuclein-mediated toxicity in cell culture [ 186 , 192 , 217 ]. PGC-1α overexpression [ 52 , 212 , 218 , 219 , 220 , 221 , 222 ] or stabilization [ 211 ] can also prevent MPTP-mediated neurotoxicity in vivo. Recently, it has also been discovered that ferulic acid can reinstate mitochondrial dynamics through PGC-1α expression modulation in 6-hydroxydopamine lesioned rats [ 223 ].…”

Mitochondrial Quality Control Strategies: Potential Therapeutic Targets for Neurodegenerative Diseases?

“…Several lines of evidence demonstrate the beneficial effects of UPR mt activation in both familial and idiopathic PD models. In SH-SY5Y cells, upregulation of UPR mt activity by overexpression of PGC-1α or ATF5 significantly improved mitochondrial function and cell survival after MPP + treatment (Cai et al, 2020;Hu et al, 2021a). UPR mt activation by ATFS-1 protected C. elegans against mutant PINK1/Parkin-induced mitochondrial fragmentation, oxidative stress, and cellular toxicity, promoting longevity and dopaminergic neuron survival (Cooper et al, 2017).…”

“…In nematode PD models, missense mutations in pink-1 / pdr-1 caused the accumulation of damaged mitochondria, which activated UPR mt to mitigate the detrimental effects of these mutations ( Cooper et al, 2017 ). Treatment of SH-SY5Y cells with mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP +) (metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [MPTP]) that selectively impairs dopaminergic neuron by inhibiting ETC complex I impaired UPR mt and induced OXPHOS stress, which could be reversed by overexpression of PGC-1α or ATF5 ( Cai et al, 2020 ; Hu et al, 2021a ).…”

ADP/ATP translocase 1 protects against an α-synuclein-associated neuronal cell damage in Parkinson’s disease model

“…Till now, the MPTP-treated PD animal models have been commonly used to unravel various pathological events and explore therapeutic mechanisms due to the similar clinical symptoms in animal to those in patients with PD, reliable and reproducible lesions in the nigrostriatal dopaminergic pathway, and less requirements for experimental technology [ 19 , 21 , 22 ]. In order to create a cellular model that mimicked PD, we exposed the neuroblastoma SH-SY5Y cells to MPP + in this study [ 23 ].…”