PINK1-associated Parkinson's disease is caused by neuronal vulnerability to calcium-induced cell death

Mol Cell. 2009 Mar 13;33(5):627-38. doi: 10.1016/j.molcel.2009.02.013.

Abstract

Mutations in PINK1 cause autosomal recessive Parkinson's disease. PINK1 is a mitochondrial kinase of unknown function. We investigated calcium homeostasis and mitochondrial function in PINK1-deficient mammalian neurons. We demonstrate physiologically that PINK1 regulates calcium efflux from the mitochondria via the mitochondrial Na(+)/Ca(2+) exchanger. PINK1 deficiency causes mitochondrial accumulation of calcium, resulting in mitochondrial calcium overload. We show that calcium overload stimulates reactive oxygen species (ROS) production via NADPH oxidase. ROS production inhibits the glucose transporter, reducing substrate delivery and causing impaired respiration. We demonstrate that impaired respiration may be restored by provision of mitochondrial complex I and II substrates. Taken together, reduced mitochondrial calcium capacity and increased ROS lower the threshold of opening of the mitochondrial permeability transition pore (mPTP) such that physiological calcium stimuli become sufficient to induce mPTP opening in PINK1-deficient cells. Our findings propose a mechanism by which PINK1 dysfunction renders neurons vulnerable to cell death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis* / drug effects
  • Apoptosis* / radiation effects
  • Calcium / metabolism*
  • Cell Line, Tumor
  • Cells, Cultured
  • Cytosol / metabolism
  • Energy Metabolism
  • Fetal Stem Cells / drug effects
  • Fetal Stem Cells / enzymology*
  • Fetal Stem Cells / pathology
  • Fetal Stem Cells / radiation effects
  • Glucose Transport Proteins, Facilitative / metabolism
  • Homeostasis
  • Humans
  • Membrane Potential, Mitochondrial
  • Mesencephalon / embryology
  • Mesencephalon / enzymology
  • Mice
  • Mice, Knockout
  • Mitochondria / drug effects
  • Mitochondria / enzymology*
  • Mitochondria / pathology
  • Mitochondria / radiation effects
  • Mitochondrial Membrane Transport Proteins / metabolism
  • NADPH Oxidases / metabolism
  • Neurons / drug effects
  • Neurons / enzymology*
  • Neurons / pathology
  • Neurons / radiation effects
  • Oxidation-Reduction
  • Oxidative Stress
  • Parkinsonian Disorders / enzymology*
  • Parkinsonian Disorders / genetics
  • Parkinsonian Disorders / pathology
  • Protein Kinases / deficiency
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Reactive Oxygen Species / metabolism
  • Sodium-Calcium Exchanger / metabolism
  • Time Factors
  • Ultraviolet Rays

Substances

  • Glucose Transport Proteins, Facilitative
  • Mitochondrial Membrane Transport Proteins
  • RNA, Small Interfering
  • Reactive Oxygen Species
  • Sodium-Calcium Exchanger
  • mitochondrial permeability transition pore
  • NADPH Oxidases
  • Protein Kinases
  • PTEN-induced putative kinase
  • Calcium