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Metabolic reprogramming during hyperammonemia targets mitochondrial function and post-mitotic senescence

ABSTRACT: Ammonia is a cytotoxic metabolite with pleotropic molecular and metabolic effects in non-hepatic tissue/cells targeting mitochondrial oxidative function that may contribute to post-mitotic senescence. Global molecular responses were determined by analysis of unbiased data followed by experimental validation of critical functional consequences in hyperammonemic differentiated myotubes and skeletal muscle from the portacaval anastomosis (PCA) rat. Integrating whole cell transcriptome with whole cell and mitochondrial proteome from hyperammonemic myotubes identified oxidative dysfunction and senescence pathways as being the most enriched with differentially expressed genes/proteins. Hyperammonemia and ammonia-lowering result in distinct clusters of molecular responses. Functional and metabolic studies in hyperammonemic myotubes showed that defects in electron transport chain (ETC) complexes I and III, loss of supercomplex assembly, decreased ATP synthesis, increased free radical generation with oxidative modification of proteins/lipids and increased expression of senescence associated molecular phenotype (SAMP) that were partially reversed by ammonia lowering. Studies in muscle from PCA rats established physiological relevance of our cellular studies. Dysregulated ammonia metabolism causes mitochondrial dysfunction by transcriptional and translational perturbations in multiple pathways with a distinct skeletal muscle SAMP.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Rattus Norvegicus (rat) Mus Musculus (mouse)

TISSUE(S): Skeletal Muscle, Myotube

SUBMITTER: Ling Li

LAB HEAD: Srinivasan Dasarathy

PROVIDER: PXD027754 | Pride | 2021-11-22

REPOSITORIES: Pride

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Metabolic reprogramming during hyperammonemia targets mitochondrial function and post-mitotic senescence

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