title: LC3 binds externalized cardiolipin on injured mitochondria to signal mitophagy in neurons: implications for Parkinson disease.
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.
authors.affiliation: Department of Pathology; Division of Neuropathology; University of Pittsburgh School of Medicine; Pittsburgh, PA USA; The McGowan Institute for Regenerative Medicine; University of Pittsburgh School of Medicine; Pittsburgh, PA USA; The Center for Neuroscience; University of Pittsburgh School of Medicine; Pittsburgh, PA USA.
authors.forename: Charleen T
authors.initials: CT
authors.lastname: Chu
authors.affiliation: Department of Critical Care Medicine and Safar Center for Resuscitation Research; University of Pittsburgh School of Medicine; Pittsburgh, PA USA; Department of Environmental and Occupational Health and Center for Free Radical and Antioxidant Health; University of Pittsburgh School of Public Health; Pittsburgh, PA USA.
authors.forename: Hülya
authors.initials: H
authors.lastname: Bayır
authors.affiliation: Department of Environmental and Occupational Health and Center for Free Radical and Antioxidant Health; University of Pittsburgh School of Public Health; Pittsburgh, PA USA.
authors.forename: Valerian E
authors.initials: VE
authors.lastname: Kagan
mesh_terms: D000818:Animals; D001343:Autophagy; D002308:Cardiolipins / Q000378:metabolism*; D002478:Cells, Cultured; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D063306:Mitophagy / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D015398:Signal Transduction
chemical_list: D002308:Cardiolipins; D008869:Microtubule-Associated Proteins; C526109:Anxa3 protein, rat
keywords: 6-hydroxydopamine; MAP1-LC3; Parkinson; autophagy; cardiolipin; cargo recognition; mitophagy; neurodegenerative diseases; neurons; rotenone