Mitochondrial Dysfunction and Mitophagy in Parkinson's Disease: From Mechanism to Therapy

Trends Biochem Sci. 2021 Apr;46(4):329-343. doi: 10.1016/j.tibs.2020.11.007. Epub 2020 Dec 13.

Abstract

Mitochondrial dysfunction has been associated with neurodegeneration in Parkinson's disease (PD) for over 30 years. Despite this, the role of mitochondrial dysfunction as an initiator, propagator, or bystander remains undetermined. The discovery of the role of the PD familial genes PTEN-induced putative kinase 1 (PINK1) and parkin (PRKN) in mediating mitochondrial degradation (mitophagy) reaffirmed the importance of this process in PD aetiology. Recently, progress has been made in understanding the upstream and downstream regulators of canonical PINK1/parkin-mediated mitophagy, alongside noncanonical PINK1/parkin mitophagy, in response to mitochondrial damage. Progress has also been made in understanding the role of PD-associated genes, such as SNCA, LRRK2, and CHCHD2, in mitochondrial dysfunction and their overlap with sporadic PD (sPD), opening opportunities for therapeutically targeting mitochondria in PD.

Keywords: PINK1; Parkin; bioenergetics; deubiquitylase; neurodegeneration; α-synuclein.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • DNA-Binding Proteins
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Mitochondria / pathology*
  • Mitophagy*
  • Parkinson Disease* / drug therapy
  • Protein Kinases
  • Transcription Factors
  • Ubiquitin-Protein Ligases
  • alpha-Synuclein

Substances

  • CHCHD2 protein, human
  • DNA-Binding Proteins
  • SNCA protein, human
  • Transcription Factors
  • alpha-Synuclein
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Protein Kinases
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • PTEN-induced putative kinase