LC3 binds externalized cardiolipin on injured mitochondria to signal mitophagy in neurons: implications for Parkinson disease

Details

• Personal Author:
  Bayir H ; Chu CT ; Kagan VE
• Description:
  Mitophagy, or the selective clearance of mitochondria by autophagy, plays a key role in mitochondrial quality control. Due to their postmitotic nature and metabolic dependence on mitochondria, either insufficient or unchecked mitophagy is detrimental to neurons. To better understand signals that regulate this process, we treated primary rat cortical neurons with the electron transport chain complex I inhibitor rotenone to elicit mitophagy. The lipidomic profiles of mitochondria from control or injured neurons were analyzed by mass spectrometry, revealing a significant redistribution of cardiolipin (CL) from the inner mitochondrial membrane to the outer mitochondrial surface. Direct liposome-binding studies, computational modeling, and site-directed mutagenesis indicate that microtubule-associated protein 1 light chain 3 (MAP1LC3/LC3), a defining protein of autophagic membranes, binds to CL. Preventing this interaction inhibits rotenone-induced mitochondrial delivery to autophagosomes and lysosomes and attenuates mitochondrial loss as assessed by western blot. The CL-LC3 interaction is also important for mitophagy induced by other stimuli including 6-hydroxydopamine, another chemical model of Parkinson disease. Given that a conserved LC3 phosphorylation site is adjacent to key residues involved in CL binding, signaling pathways could potentially modulate this interaction to fine-tune the mitochondrial recycling response. [Description provided by NIOSH]
• Subjects:
  Animals Cells, Cultured Cytology Energy Metabolism Laboratories Lipids Nervous System Nervous System Diseases Nervous System Disorders Occupational Health Safety

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• Keywords:
  6-hydroxydopamine Animal-studies Author Keywords: Mitophagy Autophagy Cardiolipin Cargo Recognition Cell-cultures Cell-metabolism Cell-transformation Cellular-function Central-nervous-system-disorders Cytopathology Laboratory-animals MAP1-LC3 Metabolic-study Metabolism Neurodegenerative Diseases Neuromotor-disorders Neuromotor-function Neurons Parkinson Physiology Proteins Rotenone

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• ISSN:
  1554-8627
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; Pennsylvania
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  376-378
• Volume:
  10
• Issue:
  2
• NIOSHTIC Number:
  nn:20045342
• Citation:
  Autophagy 2014 Feb; 10(2):376-378
• Contact Point Address:
  Charleen T Chu, Department of Pathology; Division of Neuropathology; University of Pittsburgh School of Medicine; Pittsburgh, PA USA
• CAS Registry Number:
  Rotenone (CAS RN 83-79-4)
• Federal Fiscal Year:
  2014
• NORA Priority Area:
  Manufacturing
• Performing Organization:
  University of Pittsburgh at Pittsburgh
• Peer Reviewed:
  True
• Start Date:
  20050701
• Source Full Name:
  Autophagy
• End Date:
  20160630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:3bd32b510b3fd19409ffa111bd4ccf15298032193eecb96ca3288977022c952b738007499410269ba123ec92386f12fa40c6223f42d55d159a7ab50612c9bc2a
• Download URL:
  https://stacks.cdc.gov/view/cdc/200799/cdc_200799_DS1.pdf
• File Type:
  [PDF - 683.67 KB ]