Defective mitochondrial protein import contributes to complex I-induced mitochondrial dysfunction and neurodegeneration in Parkinson's disease
Franco Iborra, Sandra (Hospital Universitari Vall d'Hebron)
Cuadros, Thais (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Parent, Annabelle (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Romero-Gimenez, Jordi (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Vila Bover, Miquel (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Perier, Celine (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Universitat Autònoma de Barcelona

Data:	2018
Resum:	Mitochondria are the prime energy source in most eukaryotic cells, but these highly dynamic organelles are also involved in a multitude of cellular events. Disruption of mitochondrial homeostasis and the subsequent mitochondrial dysfunction plays a key role in the pathophysiology of Parkinson's disease (PD). Therefore, maintenance of mitochondrial integrity through different surveillance mechanisms is critical for neuronal survival. Here, we have studied the mitochondrial protein import system in in vitro and in vivo models of PD. Complex I inhibition, a characteristic pathological hallmark in PD, impaired mitochondrial protein import, which was associated with a downregulation of two key components of the system: translocase of the outer membrane 20 (TOM20) and translocase of the inner membrane 23 (TIM23), both in vitro and in vivo. In vitro, those changes were associated with OXPHOS protein downregulation, accumulation of aggregated proteins inside mitochondria and downregulation of mitochondrial chaperones. Most of these pathogenic changes, including mitochondrial dysfunction and dopaminergic cell death, were abrogated by TOM20 or TIM23 overexpression, in vitro. However, in vivo, while TOM20 overexpression exacerbated neurodegeneration in both substantia nigra (SN) pars compacta (pc) and striatum, overexpression of TIM23 partially protected dopaminergic neurons in the SNpc. These results highlight mitochondrial protein import dysfunction and the distinct role of two of their components in the pathogenesis of PD and suggest the need for future studies to further characterize mitochondrial protein import deficit in the context of PD.
Ajuts:	Ministerio de Economía, Industria y Competitividad SAF2013-43158-R Ministerio de Educación, Cultura y Deporte FPU13/01339 Ministerio de Economía, Industria y Competitividad SAF2016-77541-R
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Cell death and disease, Vol. 9 (november 2018) , ISSN 2041-4889

DOI: 10.1038/s41419-018-1154-0
PMID: 30405116

17 p, 2.7 MB

El registre apareix a les col·leccions:
Articles > Articles de recerca
Articles > Articles publicats