Mito-metformin protects against mitochondrial dysfunction and dopaminergic neuronal degeneration by activating upstream PKD1 signaling in cell culture and MitoPark animal models of Parkinson’s disease

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dc.contributor.authorAy, Muhammet
dc.contributor.authorCharli, Adhithiya
dc.contributor.authorLangley, Monica R.
dc.contributor.authorJang, Ahyoung
dc.contributor.authorPadhi, Piyush
dc.contributor.authorJin, Huajun
dc.contributor.authorAnantharam, Vellareddy
dc.date.accessioned2026-01-24T12:20:49Z
dc.date.available2026-01-24T12:20:49Z
dc.date.issued2024
dc.departmentAlanya Alaaddin Keykubat Üniversitesi
dc.description.abstractImpaired mitochondrial function and biogenesis have strongly been implicated in the pathogenesis of Parkinson’s disease (PD). Thus, identifying the key signaling mechanisms regulating mitochondrial biogenesis is crucial to developing new treatment strategies for PD. We previously reported that protein kinase D1 (PKD1) activation protects against neuronal cell death in PD models by regulating mitochondrial biogenesis. To further harness the translational drug discovery potential of targeting PKD1-mediated neuroprotective signaling, we synthesized mito-metformin (Mito-Met), a mitochondria-targeted analog derived from conjugating the anti-diabetic drug metformin with a triphenylphosphonium functional group, and then evaluated the preclinical efficacy of Mito-Met in cell culture and MitoPark animal models of PD. Mito-Met (100–300 nM) significantly activated PKD1 phosphorylation, as well as downstream Akt and AMPK? phosphorylation, more potently than metformin, in N27 dopaminergic neuronal cells. Furthermore, treatment with Mito-Met upregulated the mRNA and protein expression of mitochondrial transcription factor A (TFAM) implying that Mito-Met can promote mitochondrial biogenesis. Interestingly, Mito-Met significantly increased mitochondrial bioenergetics capacity in N27 dopaminergic cells. Mito-Met also reduced mitochondrial fragmentation induced by the Parkinsonian neurotoxicant MPP+ in N27 cells and protected against MPP+-induced TH-positive neurite loss in primary neurons. More importantly, Mito-Met treatment (10 mg/kg, oral gavage for 8 week) significantly improved motor deficits and reduced striatal dopamine depletion in MitoPark mice. Taken together, our results demonstrate that Mito-Met possesses profound neuroprotective effects in both in vitro and in vivo models of PD, suggesting that pharmacological activation of PKD1 signaling could be a novel neuroprotective translational strategy in PD and other related neurocognitive diseases. © © 2024 Ay, Charli, Langley, Jang, Padhi, Jin, Anantharam, Kalyanaraman, Kanthasamy and Kanthasamy.
dc.description.sponsorshipNational Institutes of Health, NIH, (ES010586, ES026892, ES027245, NS074443, NS121692); National Institutes of Health, NIH
dc.identifier.doi10.3389/fnins.2024.1356703
dc.identifier.issn1662-4548
dc.identifier.scopus2-s2.0-85186547752
dc.identifier.scopusqualityQ2
dc.identifier.urihttps://doi.org/10.3389/fnins.2024.1356703
dc.identifier.urihttps://hdl.handle.net/20.500.12868/4590
dc.identifier.volume18
dc.indekslendigikaynakScopus
dc.language.isoen
dc.publisherFrontiers Media SA
dc.relation.ispartofFrontiers in Neuroscience
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.snmzKA_Scopus_20260121
dc.subjectmetformin
dc.subjectmitochondria
dc.subjectmitochondrial biogenesis
dc.subjectMitoPark
dc.subjectneuroprotection
dc.subjectParkinson’s disease
dc.subjectPKD1
dc.titleMito-metformin protects against mitochondrial dysfunction and dopaminergic neuronal degeneration by activating upstream PKD1 signaling in cell culture and MitoPark animal models of Parkinson’s disease
dc.typeArticle

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