title: Allogeneic/xenogeneic transplantation of peptide-labeled mitochondria in Parkinson's disease: restoration of mitochondria functions and attenuation of 6-hydroxydopamine-induced neurotoxicity.
abstract: Although restoration of mitochondrial function in mitochondrial diseases through peptide-mediated allogeneic mitochondrial delivery (PMD) has been demonstrated in vitro, the in vivo therapeutic efficacy of PMD in Parkinson's disease (PD) has yet to be determined. In this study, we compared the functionality of mitochondrial transfer with or without Pep-1 conjugation in neurotoxin (6-hydroxydopamine, 6-OHDA)-induced PC12 cells and PD rat models. We injected mitochondria into the medial forebrain bundle (MFB) of the PD rats after subjecting the nigrostriatal pathway to a unilateral 6-OHDA lesion for 21 days, and we verified the effectiveness of the mitochondrial graft in enhancing mitochondrial function in the soma of the substantia nigra (SN) neuron through mitochondrial transport dynamics in the nigrostriatal circuit. The result demonstrated that only PMD with allogeneic and xenogeneic sources significantly sustained mitochondrial function to resist the neurotoxin-induced oxidative stress and apoptotic death in the rat PC12 cells. The remaining cells exhibited a greater capability of neurite outgrowth. Furthermore, allogeneic and xenogeneic transplantation of peptide-labeled mitochondria after 3 months improved the locomotive activity in the PD rats. This increase was accompanied by a marked decrease in dopaminergic neuron loss in the substantia nigra pars compacta (SNc) and consistent enhancement of tyrosine hydroxylase-positive immunoreaction of dopaminergic neurons in the SNc and striatum. We also observed that in the SN dopaminergic neuron in the treated PD rats, mitochondrial complex I protein and mitochondrial dynamics were restored, thus ameliorating the oxidative DNA damage. Moreover, we determined signal translocation of graft allogeneic mitochondria from the MFB to the calbindin-positive SN neuron, which demonstrated the regulatory role of mitochondrial transport in alleviating 6-OHDA-induced degeneration of dopaminergic neurons.
authors.affiliation: Vascular and Genomic Center, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Jui-Chih
authors.initials: JC
authors.lastname: Chang
authors.affiliation: Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Shey-Lin
authors.initials: SL
authors.lastname: Wu
authors.affiliation: Vascular and Genomic Center, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Ko-Hung
authors.initials: KH
authors.lastname: Liu
authors.affiliation: Vascular and Genomic Center, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Chieh-Sen
authors.initials: CS
authors.lastname: Chuang
authors.affiliation: Department of Medical Research, Stem Cell Center, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: Fu-Chou
authors.initials: FC
authors.lastname: Cheng
authors.affiliation: Department of Life Sciences, National Chung-Hsing University, Taichung, Taiwan.
authors.forename: Hong-Lin
authors.initials: HL
authors.lastname: Su
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Life Sciences, National Yang-Ming University, Taipei, Taiwan; Department of Medicine, Mackay Medical College, Taipei, Taiwan.
authors.forename: Yau-Huei
authors.initials: YH
authors.lastname: Wei
authors.affiliation: Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Shou-Jen
authors.initials: SJ
authors.lastname: Kuo
authors.affiliation: Vascular and Genomic Center, Changhua Christian Hospital, Changhua, Taiwan; Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan; Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan. Electronic address: liu48111@gmail.com.
authors.forename: Chin-San
authors.initials: CS
authors.lastname: Liu
mesh_terms: D000818:Animals; D064026:Calbindins / Q000378:metabolism; D017690:Cell Transplantation; D003543:Cysteamine / Q000031:analogs & derivatives* / Q000737:chemistry; D059290:Dopaminergic Neurons / Q000473:pathology; D005260:Female; D006801:Humans; D008928:Mitochondria / Q000502:physiology / Q000637:transplantation*; D018384:Oxidative Stress; D016627:Oxidopamine / Q000009:adverse effects* / Q000737:chemistry; D016716:PC12 Cells; D010300:Parkinson Disease / Q000473:pathology / Q000628:therapy*; D010455:Peptides / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014183:Transplantation, Heterologous / Q000379:methods; D014184:Transplantation, Homologous / Q000379:methods
chemical_list: D064026:Calbindins; C503924:Pep-1 peptide; D010455:Peptides; D003543:Cysteamine; D016627:Oxidopamine