Mitochondrial dynamics and VMP1-related selective mitophagy in experimental acute pancreatitis

VANASCO, VIRGINIA; ROPOLO, ALEJANDRO; GRASSO, DANIEL; OJEDA, DIEGO; GARCIA, NOE; VICO, TAMARA; ORQUERA, TAMARA; QUARLERI, JORGE; ALVAREZ, SILVIA; VACCARO, M. INÉS

Frontiers in Cell and Developmental Biology

Frontiers Media SA

Año: 2021

2296-634X

Mitophagy and zymophagy are selective autophagy pathways early induced in acutepancreatitis that may explain the mild, auto limited, and more frequent clinicalpresentation of this disease. Adequate mitochondrial bioenergetics is necessary forcellular restoration mechanisms that are triggered during the mild disease. However,mitochondria and zymogen contents are direct targets of damage in acute pancreatitis.Cellular survival depends on the recovering possibility of mitochondrial function andefficient clearance of damaged mitochondria. This work aimed to analyze mitochondrialdynamics and function during selective autophagy in pancreatic acinar cells during mildexperimental pancreatitis in rats. Also, using a cell model under the hyperstimulation ofthe G-coupled receptor for CCK (CCK-R), we aimed to investigate the mechanismsinvolved in these processes in the context of zymophagy. We found that duringacute pancreatitis, mitochondrial O2 consumption and ATP production significantlydecreased early after induction of acute pancreatitis, with a consequent decrease in theATP/O ratio. Mitochondrial dysfunction was accompanied by changes in mitochondrialdynamics evidenced by optic atrophy 1 (OPA-1) and dynamin-related protein 1 (DRP-1)differential expression and ultrastructural features of mitochondrial fission, mitochondrialelongation, and mitophagy during the acute phase of experimental mild pancreatitis inrats. Mitophagy was also evaluated by confocal assay after transfection with the pMITORFP-GFP plasmid that specifically labels autophagic degradation of mitochondriaand the expression and redistribution of the ubiquitin ligase Parkin1. Moreover, wereport for the first time that vacuole membrane protein-1 (VMP1) is involved andrequired in the mitophagy process during acute pancreatitis, observable not onlyby repositioning around specific mitochondrial populations, but also by detection ofmitochondria in autophagosomes specifically isolated with anti-VMP1 antibodies aswell. Also, VMP1 downregulation avoided mitochondrial degradation confirming thatVMP1 expression is required for mitophagy during acute pancreatitis. In conclusion, weidentified a novel DRP1-Parkin1-VMP1 selective autophagy pathway, which mediates the selective degradation of damaged mitochondria by mitophagy in acute pancreatitis.The understanding of the molecular mechanisms involved to restore mitochondrialfunction, such as mitochondrial dynamics and mitophagy, could be relevant in thedevelopment of novel therapeutic strategies in acute pancreatitis.