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TitleDefective mitochondrial protein import contributes to complex I-induced mitochondrial dysfunction and neurodegeneration in Parkinson's disease.
Publication TypeJournal Article
Year of Publication2018
AuthorsFranco-Iborra, Sandra, Thais Cuadros, Annabelle Parent, Jordi Romero-Gimenez, Miquel Vila, and Celine Perier
JournalCell Death Dis
Date Published2018 Nov 07

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.

Alternate JournalCell Death Dis
PubMed ID30405116
PubMed Central IDPMC6221944
Grant ListSAF2013-43158-R / / Ministerio de Ciencia y Tecnología (Ministry of Science and Technology) /
FPU13/01339 / / Ministerio de Ciencia y Tecnología (Ministry of Science and Technology) /
SAF2016-77541-R / / Ministerio de Ciencia y Tecnología (Ministry of Science and Technology) /