Defective mitochondrial protein import contributes to complex I-induced mitochondrial dysfunction and neurodegeneration in Parkinson's disease

Cell Death Dis. 2018 Nov 7;9(11):1122. doi: 10.1038/s41419-018-1154-0.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Corpus Striatum / metabolism
  • Corpus Striatum / pathology
  • Electron Transport Complex I / deficiency
  • Electron Transport Complex I / genetics*
  • Gene Expression Regulation
  • Humans
  • Male
  • Membrane Transport Proteins / deficiency
  • Membrane Transport Proteins / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • Mitochondrial Membrane Transport Proteins / deficiency
  • Mitochondrial Membrane Transport Proteins / genetics*
  • Mitochondrial Precursor Protein Import Complex Proteins
  • Neurons / metabolism
  • Neurons / pathology
  • Oxidative Phosphorylation
  • Parkinson Disease / genetics*
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology
  • Parkinsonian Disorders / genetics*
  • Parkinsonian Disorders / metabolism
  • Parkinsonian Disorders / pathology
  • Pars Compacta / metabolism
  • Pars Compacta / pathology
  • Protein Aggregates
  • Protein Transport
  • Receptors, Cell Surface / deficiency
  • Receptors, Cell Surface / genetics*
  • Signal Transduction

Substances

  • Membrane Transport Proteins
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Precursor Protein Import Complex Proteins
  • Protein Aggregates
  • Receptors, Cell Surface
  • TIMM23 protein, human
  • TOMM20 protein, human
  • Electron Transport Complex I