Skip directly to search Skip directly to A to Z list Skip directly to page options Skip directly to site content

NIOSHTIC-2 Publications Search

Search Results

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

Authors
Chu-CT; Bayir-H; Kagan-VE
Source
Autophagy 2014 Feb; 10(2):376-378
NIOSHTIC No.
20045342
Abstract
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.
Keywords
Cell-cultures; Animals; Animal-studies; Laboratory-animals; Metabolism; Metabolic-study; Neuromotor-function; Neuromotor-disorders; Cellular-function; Proteins; Central-nervous-system-disorders; Lipids; Cytopathology; Physiology; Cell-metabolism; Cell-transformation; Author Keywords: mitophagy; Parkinson; cardiolipin; rotenone; MAP1-LC3; neurons; 6-hydroxydopamine; cargo recognition; autophagy; neurodegenerative diseases
Contact
Charleen T Chu, Department of Pathology; Division of Neuropathology; University of Pittsburgh School of Medicine; Pittsburgh, PA USA
CODEN
AUTOC9
CAS No.
83-79-4
Publication Date
20140201
Document Type
Journal Article
Funding Type
Grant
Fiscal Year
2014
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-008282; M112014
Issue of Publication
2
ISSN
1554-8627
Source Name
Autophagy
State
PA
Performing Organization
University of Pittsburgh at Pittsburgh
TOP