Mitophagy in hepatocytes: Types, initiators and role in adaptive ethanol metabolism☆.

Mitophagy (mitochondrial autophagy) in hepatocytes is an essential quality control mechanism that removes for lysosomal digestion damaged, effete and superfluous mitochondria. Mitophagy has distinct variants. In type 1 mitophagy, typical of nutrient deprivation, cup-shaped sequestration membranes (phagophores) grow, surround and sequester individual mitochondria into mitophagosomes, often in coordination with mitochondrial fission. After sequestration, the outer compartment of the mitophagosome acidifies and the entrapped mitochondrion depolarizes, followed by fusion with lysosomes. By contrast, mitochondrial depolarization stimulates type 2 mitophagy, which is characterized by coalescence of autophagic microtubule-associated protein 1A/1B-light chain 3 (LC3)-containing structures on mitochondrial surfaces without the formation of a phagophore or mitochondrial fission. Oppositely to type 1 mitophagy, the inhibition of phosphoinositide-3-kinase (PI3K) does not block type 2 mitophagy. In type 3 mitophagy, or micromitophagy, mitochondria-derived vesicles (MDVs) enriched in oxidized proteins bud off from mitochondrial inner and outer membranes and incorporate into multivesicular bodies by vesicle scission into the lumen. In response to ethanol feeding, widespread ethanol-induced hepatocellular mitochondrial depolarization occurs to facilitate hepatic ethanol metabolism. As a consequence, type 2 mitophagy develops in response to the mitochondrial depolarization. After chronic high ethanol feeding, processing of depolarized mitochondria by mitophagy becomes compromised, leading to release of mitochondrial damage-associated molecular patterns (mtDAMPs) that promote inflammatory and profibrogenic responses. We propose that the persistence of mitochondrial responses for acute ethanol metabolism links initial adaptive ethanol metabolism to mitophagy and then to chronic maladaptive changes initiating onset and the progression of alcoholic liver disease (ALD).