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2014 ; 10
(2
): 376-8
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LC3 binds externalized cardiolipin on injured mitochondria to signal mitophagy in
neurons: implications for Parkinson disease
#MMPMID24351649
Chu CT
; Bay?r H
; Kagan VE
Autophagy
2014[Feb]; 10
(2
): 376-8
PMID24351649
show ga
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.