Year: 2013
Type: article
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.
Source: Autophagy
DOI: 10.4161/auto.27191
Authors: Charleen T Chu, Hülya Bayır, Valerian E Kagan
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: National Institutes of Health, U.S. Public Health Service, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, National Institute for Occupational Safety and Health
Awards: G1144773292, G1341585006, G1474792310, G1571540551, G1571700926, G3003192447, G3047018391, G306747657, G3395651213, G3622627524, G416637570, G4231998872, G4488204751, G5204224416, Oxidative Lipidomics in Pediatric Traumatic Brain Injury, G5902375727, PINK1 Regulation of Neuronal and Mitochondrial Homeostasis, G8050382554, G8150329667, G8540167683, PINK1 regulation of neuronal and mitochondrial homeostasis, G9000033370, G9000039968, G9000057125, G9000119229, G9000228483, G9000298280, G9000306833, G9000307282, Lipid Imaging in Traumatic Brain Injury by High Resolution GCIB-secondary Ion Mass Spectrometry
OpenAlex ID: W1992091494