title: Differential regional and subtype-specific vulnerability of enteric neurons to mitochondrial dysfunction.
abstract: Mitochondrial dysfunction is a central mediator of disease progression in diverse neurodegenerative diseases that often present with prominent gastrointestinal abnormalities. Gastrointestinal dysfunction in these disorders is related, at least in part, to defects in the enteric nervous system (ENS). The role of mitochondrial deficits in ENS neurodegeneration and their relative contribution to gastrointestinal dysfunction, however, are unclear. To better understand how mitochondrial abnormalities in the ENS influence enteric neurodegeneration and affect intestinal function, we generated mice (Tfam-ENSKOs) with impaired mitochondrial metabolism in enteric neurons and glia through the targeted deletion of the mitochondrial transcription factor A gene (Tfam). Tfam-ENSKO mice were initially viable but, at an early age, they developed severe gastrointestinal motility problems characterized by intestinal pseudo-obstruction resulting in premature death. This gastrointestinal dysfunction was caused by extensive, progressive neurodegeneration of the ENS involving both neurons and glia. Interestingly, mitochondrial defects differentially affected specific subpopulations of enteric neurons and regions of the gastrointestinal tract. Mitochondrial deficiency-related neuronal and glial loss was most prominent in the proximal small intestine, but the first affected neurons, nitrergic inhibitory neurons, had the greatest losses in the distal small intestine. This regional and subtype-specific variability in susceptibility to mitochondrial defects resulted in an imbalance of inhibitory and excitatory neurons that likely accounts for the observed phenotype in Tfam-ENSKO mice. Mitochondrial dysfunction, therefore, is likely to be an important driving force of neurodegeneration in the ENS and contribute to gastrointestinal symptoms in people with neurodegenerative disorders.
authors: Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors: Andreu
authors: A
authors: Viader
authors: Elizabeth C
authors: EC
authors: Wright-Jin
authors: Bhupinder P S
authors: BP
authors: Vohra
authors: Robert O
authors: RO
authors: Heuckeroth
authors: Jeffrey
authors: J
authors: Milbrandt
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D004261:DNA Replication / Q000235:genetics; D004272:DNA, Mitochondrial / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004198:Disease Susceptibility; D017615:Enteric Nervous System / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D005769:Gastrointestinal Motility / Q000235:genetics; D041981:Gastrointestinal Tract / Q000503:physiopathology; D017353:Gene Deletion; D055786:Gene Knockout Techniques; D006609:High Mobility Group Proteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D028361:Mitochondrial Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D026602:Nitrergic Neurons / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; C081930:Tfam protein, mouse